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1.
Artigo em Inglês | MEDLINE | ID: mdl-31912991

RESUMO

OBJECTIVES: This study evaluated quantitative flow ratio (QFR) to predict microvascular dysfunction (MVD) in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: QFR is a novel approach for the rapid computation of fractional flow reserve based on three-dimensional quantitative coronary angiography. We hypothesized that QFR computation could be used to predict MVD after STEMI. METHODS: Indexes such as contrast-flow QFR (cQFR), fixed-flow QFR (fQFR), and hyperemic flow velocity (HFV) were calculated in 130 STEMI patients with culprit lesion with ≥50% diameter stenosis and TIMI flow grade 2/3 in the spontaneously recanalized culprit artery on initial angiography. MVD was defined as microvascular obstruction determined by contrast-enhanced cardiac magnetic resonance at a median of 5 days after percutaneous coronary intervention. RESULTS: Patients were divided into the MVD group (76/130, 58.5%) and non-MVD group (54/130, 41.5%). Patients with MVD had higher cQFR-fQFR value (0.080 ± 0.058 vs. 0.038 ± 0.039, p < .001) and lower modeled HFV (0.096 ± 0.044 vs. 0.144 ± 0.041 m/s, p < .001). Receiver operator characteristic curve analysis revealed that both the cQFR-fQFR value (area under the curve, AUC = 0.716, p < .001) and modeled HFV (AUC = 0.805, p < .001) had high specificity and positive predictive value to predict MVD. In multivariable logistic analysis, cQFR-fQFR was identified as an independent predictor of MVD (odds ratio = 9.800, p < .001). CONCLUSIONS: This proof-of-concept study suggested that QFR computation may be a useful tool to predict MVD after STEMI (Trial Registration:NCT03780335).

2.
J Magn Reson Imaging ; 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31943526

RESUMO

BACKGROUND: The relationship between dynamic changes of myocardial injury in ST-elevation myocardial infarction (STEMI) patients and long-term prognosis is still unclear. PURPOSE: To evaluate the extracellular volume fraction (ECV) in the differentiation of reversible from irreversible myocardial injury and the prediction value of left ventricular adverse remodeling in patients with STEMI after reperfusion. STUDY TYPE: Prospective. POPULATION: Twenty-four STEMI patients after reperfusion were included FIELD STRENGTH/SEQUENCE: 3.0 T, T1 mapping, ECV, T2 -STIR, and late gadolinium enhancement (LGE). ASSESSMENT: All the patients underwent cardiac MRI at four timepoints (days 1, 3, and 7, and at 6 months). The regions of interest (ROIs) were selected at the infarcted myocardium (with/without intramyocardial hemorrhage [IMH] and microvascular obstruction [MVO]). STATISTICAL TESTS: One-way analysis of variance and the Kruskal-Wallis test were used for the statistical analysis. RESULTS: Native T1 of MI (without MVO/IMH) gradually decreased after reperfusion (P < 0.05). The ECV of MI increased during the first 3 days and then slowly declined. Native T1 of MI with MVO/IMH was the lowest (1184 msec; 1108.5-1266), while ECV (78%; 65.5-87%) was the highest, P < 0.001. Native T1 and ECV of salvageable myocardium were higher than those of the remote myocardium but lower than those of the MI without MVO or IMH (P < 0.001). ROC analysis revealed an area under the curve (AUC) of ECV (0.85, P < 0.001) for differentiating infarcted and salvageable myocardium was higher than that of native T1 mapping (AUC: 0.63, P < 0.001) in the first week after STEMI (P < 0.0001). T1 and ECV differed significantly between patients with and without left ventricle adverse remodeling (P < 0.05). DATA CONCLUSION: Dynamic temporal changes in reversibly and irreversibly damaged myocardia were differentiated via native T1 and ECV mapping after primary percutaneous coronary intervention in STEMI patients. ECV may better reflect microvascular injury severity and myocardial viability. MI with higher native T1 and ECV or with severe microvascular injury (MVO and IMH) was correlated with adverse LV remodeling. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020.

3.
Drug Discov Today ; 25(1): 177-184, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31634592

RESUMO

Allosteric drugs have several significant advantages over traditional orthosteric drugs, encompassing higher selectivity and lower toxicity. Although allosteric drugs have potential advantages as therapeutic agents to treat human diseases, allosteric drug-resistance mutations still occur, rendering these drugs ineffective. Here, we review the emergence of allosteric drug-resistance mutations with an emphasis on examples covering clinically important therapeutic targets, including Breakpoint cluster region-Abelson tyrosine kinase (Bcr-Abl), Akt kinase [also called Protein Kinase B (PKB)], isocitrate dehydrogenase (IDH), MAPK/ERK kinase (MEK), and SRC homology 2 domain-containing phosphatase 2 (SHP2). We also discuss challenges associated with tackling allosteric drug resistance and the possible strategies to overcome this issue.

4.
J Cell Mol Med ; 24(1): 260-275, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31660692

RESUMO

The vulnerable plaque is a key distinguishing feature of atherosclerotic lesions that can cause acute atherothrombotic vascular disease. This study was designed to explore the effect of autophagy on mitochondria-mediated macrophage apoptosis and vulnerable plaques. Here, we generated the mouse model of vulnerable carotid plaque in ApoE-/- mice. Application of ApoE-/- mice with rapamycin (an autophagy inducer) inhibited necrotic core formation in vulnerable plaques by decreasing macrophage apoptosis. However, 3-methyladenine (an autophagy inhibitor) promoted plaque vulnerability through deteriorating these indexes. To further explore the mechanism of autophagy on macrophage apoptosis, we used macrophage apoptosis model in vitro and found that 7-ketocholesterol (7-KC, one of the primary oxysterols in oxLDL) caused macrophage apoptosis with concomitant impairment of mitochondria, characterized by the impairment of mitochondrial ultrastructure, cytochrome c release, mitochondrial potential dissipation, mitochondrial fragmentation, excessive ROS generation and both caspase-9 and caspase-3 activation. Interestingly, such mitochondrial apoptotic responses were ameliorated by autophagy activator, but exacerbated by autophagy inhibitor. Finally, we found that MAPK-NF-κB signalling pathway was involved in autophagy modulation of 7-KC-induced macrophage apoptosis. So, we provide strong evidence for the potential therapeutic benefit of macrophage autophagy in regulating mitochondria-mediated apoptosis and inhibiting necrotic core formation in vulnerable plaques.

5.
Patient Educ Couns ; 103(1): 44-54, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31378310

RESUMO

OBJECTIVE: To review and meta-analyze the efficacy of educational counseling alone in tinnitus. METHODS: We collected randomized controlled trials (RCTs) adhered to PRISMA guidelines. Analyzed the effect of educational counseling alone versus other forms of therapy (psychological or combination) with RevMan 5.3. RESULTS: In nine trials, 582 patients receiving educational counseling alone and 759 patients receiving other psychological or combination therapies. During the 3-6 months follow-up, there was no significant difference in the tinnitus recovery rate between these two groups (OR 0.62, 95% CI 0.34-1.16, P = 0.14; I2 = 71%, P = 0.00, random-effects model). The tinnitus symptom severity rates were also similar during 1-12 months follow-up (mean difference, 3.59, 95% CI -0.56-7.74, P = 0.09) with heterogeneity among studies (I2 = 74%, P = 0.00; random-effects model). Sensitivity analysis indicated that a single trial containing almost 40% of the patients was the cause of heterogeneity. There was no significant change in tinnitus loudness at the 3 months follow-up (OR 0.84, 95% CI 0.42-1.66, P = 0.61), with no significant heterogeneity (I2 = 0%, P = 0.60). CONCLUSION: Educational counseling alone helps to improve tinnitus and related problems, and has the same effect as other psychological or combination therapies. PRACTICE IMPLICATIONS: The results of the current analysis may help to develop evidence-based cost-effective treatment(s) for tinnitus, which will be minimally burdensome for the patients.

6.
Acad Radiol ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31780393

RESUMO

PURPOSE: The following study evaluated the diagnostic value of myocardial perfusion in patients with acute myocardial infarction (AMI) and "infarct-like myocarditis" using Intravoxel Incoherent Motion-Diffusion Weighted Imaging (IVIM-DWI imaging). METHOD: CMR data from 20 patients with suspected AMI, 20 patients with "infarct-like myocarditis" and 20 volunteers were retrospectively analyzed. IVIM-DWI data were acquired using multi-b value single-shot spin-echo echo-planar imaging sequence. IVIM-DWI data were generated according to the 16-segments AHA-model. Cine sequences covering left and right ventricle in short axis and three long axis were analyzed using a dedicated tissue-tracking algorithm. RESULTS: Overall, the AMI T2+ segments exhibited decreased apparent diffusion coefficient (ADC), ADCslow, ADC fast and f values (1.39 ± 0.23 µm2/ms, 1.36 ± 0.23 µm2/ms, 70.77 ± 7.04 µm2/ms, and 0.1243 ± 0.01, respectively) compared to infarct-like myocarditis T2+ (1.48 ± 0.11 µm2/ms, 1.44 ± 0.11 µm2/ms, 87.66 ± 12.50 µm2/ms, and 0.1411 ± 0.02, respectively) and normal controls (1.55 ± 0.07 µm2/ms, 1.52 ± 0.06 µm2/ms, 108.84 ± 4.06 µm2/ms, and 0.1599 ± 0.01, respectively) (all p < 0.05). In addition, AMI LGE+ segments showed significantly lower IVIM-DWI associated parameters (1.34 ± 0.21 µm2/ms, 1.31 ± 0.21 µm2/ms, 68.75 ± 6.33µm2/ms, and 0.1198 ± 0.01) compared to infarct-like myocarditis LGE+ (1.42 ± 0.06 µm2/ms, 1.38 ± 0.08 µm2/ms, 79.12 ± 5.70 µm2/ms, and 0.1313 ± 0.02) (p < 0.05). Moreover, left ventricular peak subendo and subepi radial, circumferential, and longitudinal strain were lower in AMI T2+ segments than in infarct-like myocarditis T2+ segments and normal controls (p < 0.05); AMI LGE+ segments exhibited the lowest strain in three orientations compared to other subgroups (p < 0.05). CONCLUSION: These findings prove that IVIM-DWI may be used as a reliable sequence for evaluation of different myocardial perfusion patterns in AMI and infarct-like myocarditis. AMI may exhibit lower myocardial perfusion status compared to infarct-like myocarditis due to different pathophysiological process.

7.
J Magn Reson Imaging ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31710415

RESUMO

BACKGROUND: The presence of late gadolinium enhanced (LGE), which may enable better evaluation of myocardial impairment, would help predict the occurrence of life-threatening arrhythmias and major adverse cardiovascular events (MACE) in patients suffering from ischemic cardiomyopathy (ICM) and nonischemic cardiomyopathy (NICM) patients and who underwent a process of implantable cardioverter-defibrillator (ICD). PURPOSE: To evaluate the prognostic value of cardiac MR-LGE for ICM and NICM patients with ICD. STUDY TYPE: Systematic review and meta-analysis. POPULATION: A total of 33 studies of 3457 patients were included. FIELD STRENGTH: 1. 5T and 3.0T, LGE. ASSESSMENT: PubMed, Cochrane Library, EMBASE, and Web of Science were systematically searched for studies reporting LGE in ICM or NICM patients with ICD implantation with several kinds of endpoints: MACE, life-threatening arrhythmia, cardiovascular mortality, and all-cause mortality. STATISTICAL TESTS: A meta-analysis was performed using a random-effects model to calculate odds ratios or standard mean differences (SMDs) for binary and continuous data. RESULTS: MR-LGE was positive in 1923 (55.6%) of ICM and NICM patients. LGE-present patients were more likely to have life-threatening arrhythmia (odds ratio [OR]: 5.1; 95% confidence interval [CI]: 3.8-6.8), MACE (OR: 5.2; 95% CI: 3.8-6.9), cardiovascular mortality (OR: 2.4; 95% CI: 1.2-4.6), and all-cause mortality (OR: 2.1; 95% CI: 1.3-3.4) compared with those without LGE. Moreover, ICM and NICM patients with LGE both had increased life-threatening arrhythmia (OR: 4.6; 95% CI: 2.7-8.0; OR: 5.2; 95% CI: 3.6-7.8, respectively) and MACE (OR: 4.7; 95% CI: 2.8-7.9; OR: 4.7; 95% CI: 2.7-8.1, respectively). DATA CONCLUSION: The presence of MR-LGE may worsen the prognosis for adverse cardiovascular events in both ICM and NIMC patients who benefit more from ICDs. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 3.

8.
J Inorg Biochem ; 203: 110909, 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31689591

RESUMO

Glioma stem cells (GSCs) are thought to be responsible for the recurrence and invasion of glioblastoma multiform (GBM), which have been evaluated and exploited as the therapeutic target for GBM. Cyclometalated iridium(III) complexes have been demonstrated as the potential anticancer agents, however, their antitumor efficacies against GSCs are still unknown. Herein, we investigated the antitumor activity of two cyclometalated iridium(III) complexes [Ir(ppy)2L](PF6) (Ir1) and [Ir(thpy)2L](PF6) (Ir2) (ppy = 2-phenylpyridine, thpy = 2-(2-thienyl)pyridine and L = 4,4'-Bis(hydroxymethyl)-2,2'-bipyridine) against GSCs. The results clearly indicate that Ir1 and Ir2 kill GSCs selectively with IC50 values ranging from 5.26-9.05 µM. Further mechanism research display that Ir1 and Ir2 can suppress the proliferation of GSCs, penetrate into GSCs efficiently, localize to mitochondria, and induce mitochondria-mediated apoptosis, including the loss of mitochondrial membrane (MMP), elevation of intracellular reactive oxygen species (ROS) and caspases activation. Moreover, Ir1 and Ir2 can destroy the GSCs self-renewal and unlimited proliferation capacity by affecting the GSCs colony formation. According our knowledge, this is the first study to investigate the anti-GSCs properties of cyclometalated iridium(III) complexes.

9.
Nanoscale ; 11(42): 19783-19790, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31612184

RESUMO

Developing robust and inexpensive non-noble metal based anode electrocatalysts is highly desirable for alkaline direct methanol fuel cells (ADMFCs). Herein, we successfully develop a facile self-template synthetic strategy for gram-grade porous NiO nanotubes (NTs) by pyrolyzing a nanorod-like Ni-dimethylglyoxime complex. The pyrolysis temperature highly correlates with the morphology and crystallinity of NiO NTs. The optimal NiO NTs exhibit a large electrochemically active surface area, a fast catalytic kinetics, and a small charge transfer resistance, which induce an outstanding electrocatalytic activity for the methanol oxidation reaction (MOR). Compared with conventional NiO nanoparticles, NiO NTs achieve a 11.5-fold increase in mass activity at 1.5 V for the MOR due to nanotubal morphology and abundant non-vacancy defects on the NiO NT surface. Moreover, NiO NTs have a higher electrocatalytic activity for the intermediates of the MOR (such as formaldehyde and formate) than conventional NiO nanoparticles, which also contribute to MOR activity enhancement. Given the facile synthesis and enhanced electrocatalytic performance, NiO NTs may be promising anode electrocatalysts for ADMFCs.

10.
Adv Mater ; : e1903808, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31566257

RESUMO

Electrodeposition induces material syntheses on conductive surfaces, distinguishing it from the widely used solid-state technologies in Li-based batteries. Electrodeposition drives uphill reactions by applying electric energy instead of heating. These features may enable electrodeposition to meet some needs for battery fabrication that conventional technologies can rarely achieve. The latest progress of electrodeposition technologies in Li-based batteries is summarized. Each component of Li-based batteries can be electrodeposited or synthesized with multiple methods. The advantages of electrodeposition are the main focus, and they are discussed in comparison with traditional technologies with the expectation to inspire innovations to build better Li-based batteries. Electrodeposition coats conformal films on surfaces and can control the film thickness, providing an effective approach to enhancing battery performance. Engineering interfaces by electrodeposition can stabilize the solid electrolyte interphase (SEI) and strengthen the adhesion of active materials to substrates, thereby prolonging the battery longevity. Lastly, a perspective of future studies on electrodepositing batteries is provided. The significant merits of electrodeposition should greatly advance the development of Li-based batteries.

12.
BMJ Open ; 9(9): e024290, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31558447

RESUMO

INTRODUCTION: The detection rate of somatic symptom disorder (SSD) in general hospitals is unsatisfactory. Self-report questionnaires that assess both somatic symptoms and psychological characteristics will improve the process of screening for SSD. The Somatic Symptom Scale-China (SSS-CN) questionnaire has been developed to meet this urgent clinical demand. The aim of this research is to validate the self-reported SSS-CN as a timely and practical instrument that can be used to identify SSD and to assess the severity of this disorder. METHODS AND ANALYSIS: At least 852 patients without organic disease but presenting physical discomfort will be recruited at a general hospital. Each patient will undergo a Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)-guided physician diagnosis, including disease identification and severity assessment, as the reference standard. This research will compare the diagnostic performance of the SSS-CN for SSD, the Patient Health Questionnaire-15 (PHQ-15) and other SSD-related questionnaires. Statistical tests to measure the area under the curve (AUC) and volume under the surface of the receiver operating curve will be used to assess the accuracy of the SSD identification and the severity assessment, respectively. In addition to this standard diagnostic study, we will conduct follow-up investigations to explore the effectiveness of the SSS-CN in monitoring treatment effects. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Renji Hospital Human Research Ethics Committee, approval number 2 015 016. The findings of this study will be disseminated via peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: NCT03513185.

13.
ACS Appl Mater Interfaces ; 11(40): 36589-36597, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31513743

RESUMO

Solar-driven interfacial water evaporation is regarded as an effective, renewable, and environment-friendly technology for clean water production. However, biofouling caused by the nonspecific interaction between the steam generator and biofoulants generally hinders the efficient application of wastewater treatment. Herein, this work reports a facile strategy to fabricate flexible anti-biofouling fibrous photothermal membrane consisting of a MXene-coated cellulose membrane for highly efficient solar-driven water steam evaporation toward water purification applications. The as-prepared MXene/cellulose photothermal membrane exhibits light absorption efficiency as high as ∼94% in a wide solar spectrum range and a water evaporation rate up to 1.44 kg m-2 h-1 under one solar illumination. Also, the MXene/cellulose membrane shows very high antibacterial efficiency (above 99.9%) owing to the MXene coating as a highly effective bacteriostatic agent. Such a flexible, anti-biofouling, and high-efficiency photothermal membrane sheds light on practical applications in long-term wastewater treatments.

14.
J Mol Cell Cardiol ; 136: 72-84, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31491377

RESUMO

Mitochondria are involved in multiple cellular functions, in addition to their core role in energy metabolism. Mitochondria localized in different cellular locations may have different morphology, Ca2+ handling and biochemical properties and may interact differently with other intracellular structures, causing functional specificity. However, most prior studies have utilized isolated mitochondria, removed from their intracellular environment. Mitochondria in cardiac ventricular myocytes are highly organized, with a majority squeezed between the myofilaments in longitudinal chains (intrafibrillar mitochondria, IFM). There is another population of perinuclear mitochondria (PNM) around and between the two nuclei typical in myocytes. Here, we take advantage of live myocyte imaging to test for quantitative morphological and functional differences between IFM and PNM with respect to calcium fluxes, membrane potential, sensitivity to oxidative stress, shape and dynamics. Our findings show higher mitochondrial Ca2+ uptake and oxidative stress sensitivity for IFM vs. PNM, which may relate to higher local energy demand supporting the contractile machinery. In contrast to IFM which are remarkably static, PNM are relatively mobile, appear to participate readily in fission/fusion dynamics and appear to play a central role in mitochondrial genesis and turnover. We conclude that while IFM may be physiologically tuned to support local myofilament energy demands, PNM may be more critical in mitochondrial turnover and regulation of nuclear function and import/export. Thus, important functional differences are present in intrafibrillar vs. perinuclear mitochondrial subpopulations.

15.
Int Immunopharmacol ; 76: 105874, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499270

RESUMO

Pulmonary arterial hypertension (PAH) is a severe complication of systemic lupus erythematosus (SLE), with unclear etiopathogenesis. We evaluated the role of macrophage migration inhibitory factor (MIF), which has been implicated in idiopathic pulmonary hypertension (PH), in SLE-associated PAH. Circulating MIF was measured in SLE patients, SLE-PAH patients, and healthy donors. In situ pulmonary artery MIF protein expression was determined in spontaneous SLE mice (MRL/lpr) and hypoxia-induced C57BL/6J mice. Daily MIF098 was administered to C57BL/6J mice, and these mice were maintained in a hypoxic chamber for 4 weeks. The right ventricular systolic pressure (RVSP) and pathological characteristics of the pulmonary artery (PA), such as hyperproliferation, muscularization, and fibrosis were then measured in each group of mice. Data were also obtained in vitro using pulmonary smooth muscle cells (PASMC) challenged with platelet-derived growth factor (PDGF)-BB or 1% O2 hypoxia. As a result, circulating MIF was elevated in SLE-PAH patients compared with SLE patients or healthy donors. Higher RVSP SLE mice produced more MIF protein than lower RVSP SLE mice in the pulmonary artery. MIF098 decreased RVSP and inhibited distal pulmonary artery hyperproliferation, muscularization, and collagen deposition in hypoxia challenged mice. In addition, MIF098 inhibited PASMC proliferation and migration by regulating mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK1/2) signal- and cell-cycle-related proteins. MIF098 also reduced collagen synthesis by inhibiting the TGFß1/Smad2/Smad3 pathway in cell-based experiments. In conclusion, MIF may serve as a biomarker and a therapeutic target of SLE-associated PAH. Pharmacologic MIF antagonism may be an effective means to ameliorate SLE-PAH.

16.
Theranostics ; 9(15): 4461-4473, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31285773

RESUMO

Background: Vitamin C has been demonstrated to kill BRAF mutant colorectal cancer cells selectively. BRAF mutation is the most common genetic alteration in thyroid tumor development and progression; however, the antitumor efficacy of vitamin C in thyroid cancer remains to be explored. Methods: The effect of vitamin C on thyroid cancer cell proliferation and apoptosis was assessed by the MTT assay and flow cytometry. Xenograft and transgenic mouse models were used to determine its in vivo antitumor activity of vitamin C. Molecular and biochemical methods were used to elucidate the underlying mechanisms of anticancer activity of vitamin C in thyroid cancer. Results: Pharmaceutical concentration of vitamin C significantly inhibited thyroid cancer cell proliferation and induced cell apoptosis regardless of BRAF mutation status. We demonstrated that the elevated level of Vitamin C in the plasma following a high dose of intraperitoneal injection dramatically inhibited the growth of xenograft tumors. Similar results were obtained in the transgenic mouse model. Mechanistically, vitamin C eradicated BRAF wild-type thyroid cancer cells through ROS-mediated decrease in the activity of EGF/EGFR-MAPK/ERK signaling and an increase in AKT ubiquitination and degradation. On the other hand, vitamin C exerted its antitumor activity in BRAF mutant thyroid cancer cells by inhibiting the activity of ATP-dependent MAPK/ERK signaling and inducing proteasome degradation of AKT via the ROS-dependent pathway. Conclusions: Our data demonstrate that vitamin C kills thyroid cancer cells by inhibiting MAPK/ERK and PI3K/AKT pathways via a ROS-dependent mechanism and suggest that pharmaceutical concentration of vitamin C has potential clinical use in thyroid cancer therapy.

17.
Artigo em Inglês | MEDLINE | ID: mdl-31195162

RESUMO

BACKGROUND & AIMS: There is controversy over whether use of non-vitamin K antagonist oral anticoagulants (NOACs) associates with increased risk of major gastrointestinal bleeding (GIB) compared with conventional therapies (such as vitamin K antagonists or anti-platelet agents). We performed a systematic review and meta-analysis of data from randomized controlled trials and high-quality real-world studies. METHODS: We performed a systematic search of the MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov Website databases (through Oct 12, 2018) for randomized controlled trials and high-quality real-world studies that reported major GIB events in patients given NOACs or conventional therapy. Relative risks (RRs) for randomized controlled trials and adjusted hazard ratios (aHRs) for real-world studies were calculated separately using random-effects models. RESULTS: We analyzed data from 43 randomized controlled trials (183,752 patients) and 41 real-world studies (1,879,428 patients). The pooled major rates of GIB for patients on NOACs (1.19%) vs conventional treatment (0.92%) did not differ significantly (RR from randomized controlled trials, 1.09; 95% CI, 0.91-1.31 and aHR from real-world studies, 1.02; 95% CI, 0.94-1.10; Pinteraction=.52). Rivaroxaban, but not other NOACs, was associated with an increased risk for major GIB (RR from randomized controlled trials, 1.39; 95% CI, 1.17-1.65 and aHR from real-world studies, 1.14; 95% CI, 1.04-1.23; Pinteraction = .06). Analyses of subgroups, such as patients with different indications, dosage, or follow-up time, did not significantly affect results. Meta-regression analysis failed to detect any potential confounding to impact the primacy outcome. CONCLUSIONS: In a systematic review and meta-analysis of data from randomized controlled trials and real-world studies, we confirmed that there is no significant difference in risk of major GIB between patients receiving NOACs vs conventional treatment. Rivaroxaban users had a 39% increase in risk for major GIB.

18.
J Cell Physiol ; 234(12): 21915-21924, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31041827

RESUMO

Diabetic retinopathy (DR) remains the leading cause of blindness in adults with diabetes mellitus. Numerous microRNAs (miRNAs) have been identified to modulate the pathogenesis of DR. The main purpose of this study was to evaluate the potential roles of miR-455-5p in high glucose (HG)-treated retinal pigment epithelial (RPE) cells and underlying mechanisms. Our present investigation discovered that the expression of miR-455-5p was apparently downregulated in ARPE-19 cells stimulated with HG. In addition, forced expression of miR-455-5p markedly enhanced cell viability and restrained HG-induced apoptosis accompanied by decreased BCL2-associated X protein (Bax)/B-cell leukemia/lymphoma 2 (Bcl-2) ratio and expression of apoptotic marker cleaved caspase-3 during HG challenged. Subsequently, augmentation of miR-455-5p remarkably alleviated HG-triggered oxidative stress injury as reflected by decreased the production of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) content as well as NADPH oxidase 4 expression, concomitant with enhanced the activities of superoxide dismutase, catalase, and GPX stimulated with HG. Furthermore, enforced expression of miR-455-5p effectively ameliorated HG-stimulated inflammatory response as exemplified by repressing the secretion of inflammatory cytokines interleukin 1ß (IL-1ß), IL-6, and tumour necrosis factor-α in ARPE-19 cells challenged by HG. Most importantly, we successfully identified suppressor of cytokine signaling 3 (SOCS3) as a direct target gene of miR-455-5p, and miR-455-5p negatively regulated the expression of SOCS3. Mechanistically, restoration of SOCS3 abrogated the beneficial effects of miR-455-5p on apoptosis, accumulation of ROS, and inflammatory factors production in response to HG. Taken together, these findings demonstrated that miR-455-5p relieved HG-induced damage through repressing apoptosis, oxidant stress, and inflammatory response by targeting SOCS3. The study gives evidence that miR-455-5p may serve as a new potential therapeutic agent for DR treatment.

19.
BMC Cardiovasc Disord ; 19(1): 128, 2019 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-31142268

RESUMO

BACKGROUND: The association between mean platelet volume (MPV) and coronary plaque vulnerability in patients with non-ST-elevation ACS (NSTE-ACS) has not been investigated. We performed a retrospective study to evaluate the association between MPV and plaque vulnerability using optical coherence tomography (OCT). METHODS: Consecutive NSTE-ACS patients who underwent pre-intervention OCT examination in our center were included in this study. Features of coronary plaques in the culprit arteries were classified as rupture, nonrupture with thin-cap fibroatheroma (TCFA), and nonrupture and non-TCFA. ROC analyses were used to determine the predictive efficacy of MPV for plaque rupture, and multivariate logistic regression analysis was performed to evaluate the potential independent predictors of plaque vulnerability. RESULTS: Overall, 94 patients were included in this study. We identified 17 patients with plaque rupture, 10 with nonrupture with TCFA, and 67 with nonrupture and non-TCFA. ROC analyses showed that MPV ≥ 10.5 fL was predictive of plaque rupture in NSTE-ACS patients. Univariate analyses indicated that patients with higher MPV (≥ 10.5 fL) had higher body mass index and poorer lipid profiles compared to those with lower MPV. Moreover, those with higher MPV had higher incidences of plaque rupture and thrombosis (both P < 0.05). Results of multivariate analyses showed that diabetes and higher platelet distribution width (PDW) were independent risk factors of TCFA (P = 0.032 and 0.046, respectively), while diabetes, higher BMI, higher PDW, and higher MPV were independent determinants of plaque rupture in our cohorts (P all < 0.05). CONCLUSIONS: Higher MPV is independently associated with higher risk of plaque rupture as evidenced by OCT in our cohort of NSTE-ACS patients.

20.
J Pineal Res ; 67(2): e12581, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31009101

RESUMO

Rupture of vulnerable plaques is the main trigger of acute cardio-cerebral vascular events, but mechanisms responsible for transforming a stable atherosclerotic into a vulnerable plaque remain largely unknown. Melatonin, an indoleamine hormone secreted by the pineal gland, plays pleiotropic roles in the cardiovascular system; however, the effect of melatonin on vulnerable plaque rupture and its underlying mechanisms remains unknown. Here, we generated a rupture-prone vulnerable carotid plaque model induced by endogenous renovascular hypertension combined with low shear stress in hypercholesterolemic ApoE-/- mice. Melatonin (10 mg/kg/d by oral administration for 9 weeks) significantly prevented vulnerable plaque rupture, with lower incidence of intraplaque hemorrhage (42.9% vs. 9.5%, P = 0.014) and of spontaneous plaque rupture with intraluminal thrombus formation (38.1% vs. 9.5%, P = 0.029). Mechanistic studies indicated that melatonin ameliorated intraplaque inflammation by suppressing the differentiation of intraplaque macrophages toward the proinflammatory M1 phenotype, and circadian nuclear receptor retinoid acid receptor-related orphan receptor-α (RORα) mediated melatonin-exerted vasoprotection against vulnerable plaque instability and intraplaque macrophage polarization. Further analysis in human monocyte-derived macrophages confirmed the role of melatonin in regulating macrophage polarization by regulating the AMPKα-STATs pathway in a RORα-dependent manner. In summary, our data provided the first evidence that melatonin-RORα axis acts as a novel endogenous protective signaling pathway in the vasculature, regulates intraplaque inflammation, and stabilizes rupture-prone vulnerable plaques.


Assuntos
Aterosclerose/metabolismo , Macrófagos/metabolismo , Melatonina/farmacologia , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Placa Aterosclerótica/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/patologia , Humanos , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout para ApoE , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Transdução de Sinais/genética
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