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1.
Crit Care Med ; 82(11): 827-834, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31693532

RESUMO

BACKGROUND: Data on whether different transcatheter aortic valve replacement (TAVR) devices and delivery approaches can achieve equally favorable outcomes when performed by a single heart team are scarce. We sought to compare the performance and short-term outcomes of three different TAVR devices-self-expanding Medtronic CoreValve (MCV), mechanically expanded Lotus valve, and balloon-expandable Edwards SAPIEN XT (SXT)-for the treatment of severe aortic stenosis (AS) in a single large-volume center in Taiwan. METHODS: We retrospectively reviewed consecutive patients who underwent TAVR for the treatment of severe AS. Clinical outcomes were reported following Valve Academic Research Consortium 2 (VARC-2) criteria. The composite primary endpoint was combined all-cause mortality, myocardial infarction (MI), or disabling stroke within 180 days. RESULTS: A total of 231 patients (MCV n=112, Lotus n=18, and SXT n=101) were included. The device and procedural success rates were similar among all three TAVR devices. At 30 days, there was no significant difference in all-cause mortality, cardiovascular mortality, periprocedural MI, stroke, major vascular complications, life-threatening bleeding, acute kidney injury (AKI, stage 2/3), or VARC-2 composite early safety endpoints. There was no difference among groups in the rate of primary endpoint within 180 days. Lack of procedural success, presence of acute coronary occlusion during TAVR, and presence of AKI (stage 3) after TAVR were independent predictors of adverse outcomes. CONCLUSION: TAVR using MCV, Lotus, or SXT was associated with similar 30- and 180-day clinical outcomes. The presence of periprocedural complications was one of the main determinants of short-term adverse outcomes.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31701352

RESUMO

The enhanced activity of endothelial progenitor cells (EPCs) by AMP-activated protein kinase (AMPK) agonists might explain the reversal of chronic heart failure (CHF)-mediated endothelial dysfunction. We studied baseline circulating EPC numbers in patients with heart failure and clarified the effect of fenofibrate on both circulating angiogenic cell (CAC) and late EPC activity. The numbers of circulating EPCs in CHF patients were quantified by flow cytometry. Blood-derived mononuclear cells were cultured, and CAC and late EPC functions, including fibronectin adhesion, tube formation, and migration, were evaluated. We focused on the effect of fenofibrate, an AMPK agonist, on EPC function and Akt/eNOS cascade activation in vitro. The number of circulating EPCs (CD34+/KDR+) was significantly lower in CHF patients (ischemic cardiomyopathy (ICMP): 0.07%, dilated cardiomyopathy (DCMP): 0.068%; p < 0.05) than in healthy subjects (0.102% of the gating region). In CACs, fibronectin adhesion function was reversed by fenofibrate treatment (p < 0.05). Similar results were also found for tube formation and migration in late EPCs, which were significantly improved by fenofibrate in an AMPK-dependent manner (p < 0.05), suggesting that fenofibrate reversed CACs and late EPC dysfunction in CHF patients. The present findings reveal the potential application of the AMPK agonist fenofibrate to reverse endothelial dysfunction in CHF patients.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31574058

RESUMO

STUDY DESIGN: Retrospective study from a prospectively collected database. OBJECTIVE: To compare the perioperative outcome between after-hours and daytime surgery carried out by a dedicated spinal deformity team for severe Idiopathic Scoliosis (IS) patients with Cobb angle ≥ 90°. SUMMARY OF BACKGROUND DATA: There were concerns that after-hours corrective surgeries in severe IS have higher morbidity compared to daytime surgeries. METHODS: Seventy-one severe IS patients who underwent single-staged Posterior Spinal Fusion were included. Surgeries performed between 08:00H and 16:59H were classified as 'daytime' group and surgeries performed between 17:00H and 06:00H were classified as 'after-hours' group. Perioperative outcome parameters were average operation time in and out, operation duration, intraoperative blood loss, intraoperative hemodynamic parameters, preoperative and postoperative hemoglobin, blood transfusion rate, total patient-controlled anesthesia (PCA) morphine usage, length of postoperative hospitalization and complications. Radiological variables assessed were preoperative and postoperative Cobb angle, side bending flexibility, number of fusion levels, number of screws used, correction rate and Side Bending Correction Index (SBCI). RESULTS: Thirty patients were operated during daytime and 41 patients operated after-hours. The mean age was 16.1 ±â€Š5.8 years old. The mean operation time in for daytime group was 11:31 ±â€Š2:45H versus 19:10 ±â€Š1:24H for after-hours group. There were no significant differences between both groups in the operation duration, intraoperative blood loss, intraoperative hemodynamic parameters, postoperative hemoglobin, hemoglobin drift, transfusion rate, length of postoperative hospitalization, postoperative Cobb angle, correction rate and SBCI. There were four complications (1 SSEP loss, 1 massive blood loss and 2 superficial wound infections) with no difference between daytime and after-hours group. CONCLUSION: After-hours elective spine deformity corrective surgeries in healthy ambulatory patients with severe IS performed by a dedicated spinal deformity team using dual attending surgeon strategy were as safe as those performed during daytime. LEVEL OF EVIDENCE: 4.

4.
J Orthop Surg (Hong Kong) ; 27(3): 2309499019879213, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31615339

RESUMO

Aberrant left brachiocephalic vein is a rare condition. Its occurrence in patients requiring anterior cervicothoracic approach for severe kyphoscoliosis has not been described. A 16-year-old male with neurofibromatosis and severe upper thoracic kyphoscoliosis presented to us with curve progression. Halo gravity traction was attempted but failed to achieve significant correction. Subsequently, he underwent halo-pelvic traction and later Posterior Spinal Fusion (PSF) from C2 to T10. Second-stage anterior cervicothoracic approach with anterior fibula strut grafting was planned; however, preoperative computed tomography angiography revealed an aberrant left brachiocephalic vein with an anomalous retrotracheal and retroesophageal course, directly anterior to the T5/T6 vertebrae (planned anchor site for fibula strut graft) before draining into superior vena cava. Therefore, surgery was abandoned due to the risks associated with this anomaly. Aberrant left brachiocephalic vein is rare, the presence of which could be a contraindication for anterior cervicothoracic approach. Assessment of the anterior neurovascular structures is crucial in preoperative planning.

5.
Aging (Albany NY) ; 11(19): 8182-8203, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31581132

RESUMO

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Recent years, circular RNA (circRNA) have been shown to exert vital functions in the pathological progressions of many diseases. A growing number of evidences have identified the representative function of exosomal circRNAs in the physiological state of donor cells, which further induces cellular responses after captured by recipient cells. However, the contributions of circRNAs to HCC remain largely unknown. In vitro and in vivo regulatory roles of circRNA Cdr1as in proliferative and migratory abilities of HCC were evaluated by CCK8, EdU, Transwell and tumourigenicity assays, respectively. Results showed circRNA Cdr1as was highly expressed in HCC cell lines and tissues. Overexpression of circRNA Cdr1as greatly accelerated HCC cells to proliferate and migrate. Mechanistically, we found that Cdr1as could promote the expression of AFP, a well-known biomarker for HCC, by sponging miR-1270. Further studies showed exosomes extracted from HCC cells overexpressing circRNA Cdr1as accelerated the proliferative and migratory abilities of surrounding normal cells. In all, circRNA Cdr1as serves as a ceRNA to promote the progression of HCC. Meanwhile, it is directly transferred from HCC cells to surrounding normal cells via exosomes to further mediate the biological functions of surrounding cells.

6.
J Cardiol ; 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31563433

RESUMO

BACKGROUND: Literature describing recovery of left ventricular (LV) function post sacubitril/valsartan treatment and the optimal management of heart failure (HF) patients receiving sacubitril/valsartan remain sparse. METHODS: We recruited 437 consecutive chronic HF patients with baseline left ventricular ejection fraction (LVEF) less than 40%, who were treated with sacubitril/valsartan. All patients underwent routine echocardiographic measurement. RESULTS: During treatment period, recovery of LVEF to 50% or greater was observed in 77 (17.6%) patients. After multivariate analysis, recovery of LV dysfunction was associated with non-ischemic etiology of HF, smaller baseline LV end-diastolic diameter (LVEDD), and higher initial dosage of sacubitril/valsartan. Compared to those without recovery of LV dysfunction, death from cardiovascular causes or first unplanned hospitalization for HF (CVD/HFH) were significantly lower in patients with LVEF recovery [11.7% vs. 24.4%, hazard ratio (HR) 0.42, p = 0.014]. Among patients with recovery of LVEF, 51 patients continued to receive the same dosage of sacubitril/valsartan had higher LVEF and were less likely to have deterioration of LVEF than the other 26 patients who received either tapering dose of sacubitril/valsartan or switching from sacubitril/valsartan to renin-angiotensin-system blockers (LVEF 56.4 ± 5.3% vs. 45.0 ± 12.8%, p < 0.001; ΔLVEF 1.2 ± 5.1% vs. -9.3 ± 12.0%, p < 0.001). CVD/HFH occurred more frequently in the taper group than the maintenance group (23.1% vs. 5.9%, HR 0.22, p = 0.035). CONCLUSIONS: Non-ischemic etiology of HF, smaller baseline LVEDD, and higher initial dosage of sacubitril/valsartan could predict better recovery of LV function. Among patients with functional recovery, tapering sacubitril/valsartan dose was associated with deterioration of recovered heart function and had less favorable prognosis during follow-up.

7.
Int J Surg Pathol ; : 1066896919873078, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31526158

RESUMO

Dedifferentiated liposarcoma rarely occurs in the esophagus. It always has atypical clinical manifestations and different pathologic features, which usually lead to misdiagnosis and mistreatment. Given its poor prognosis, early and accurate diagnosis is of the utmost importance. The accumulation of similar cases is critical for surgeons and pathologists to raise awareness of such tumors. This report aims to discuss the diagnosis and provide a reference for the clinical diagnosis and treatment for pathologists and clinicians.

8.
J Chin Med Assoc ; 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31517772

RESUMO

BACKGROUND: Data on whether different transcatheter aortic valve replacement (TAVR) devices and delivery approaches can achieve equally favorable outcomes when performed by a single heart team are scarce. We sought to compare the performance and short-term outcomes of three different TAVR devices - self-expanding Medtronic CoreValve (MCV), mechanically expanded Lotus valve (Boston Scientific), and balloon-expandable Edwards SAPIEN XT (SXT) - for the treatment of severe aortic stenosis (AS) in a single large-volume center in Taiwan. METHODS: We retrospectively reviewed consecutive patients who underwent TAVR for the treatment of severe AS. Clinical outcomes were reported following Valve Academic Research Consortium 2 (VARC-2) criteria. The composite primary endpoint was combined all-cause mortality, myocardial infarction (MI), or disabling stroke within 180 days. RESULTS: A total of 231 patients (MCV n=112, Lotus n=18, and SXT n=101) were included. The device and procedural success rates were similar among all three TAVR devices. At 30 days, there was no significant difference in all-cause mortality, cardiovascular mortality, periprocedural MI, stroke, major vascular complications, life-threatening bleeding, acute kidney injury (AKI) stage 2/3, or VARC-2 composite early safety endpoints. There was no difference among groups in rate of primary endpoint within 180 days. Lack of procedural success, presence of acute coronary occlusion during TAVR, and presence of AKI stage 3 after TAVR were independent predictors of adverse outcomes. CONCLUSION: TAVR using MCV, Lotus, or SXT was associated with similar 30-day and 180-day clinical outcomes. The presence of periprocedural complications were main determinants of short-term adverse outcomes.

9.
Atherosclerosis ; 289: 143-161, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31518965

RESUMO

BACKGROUND AND AIMS: Krüppel-like factor 14 (KLF14) is known to play a role in atherosclerosis, but the underlying mechanisms are still largely unknown. The aim of our study was to explore the effects of KLF14 on lipid metabolism and inflammatory response, providing a potential target for lowering the risk of atherosclerosis-causing disease. METHODS AND RESULTS: mRNA and protein levels of KLF14 were significantly decreased in oxidized low-density lipoprotein (oxLDL)-treated macrophages and in the atherosclerotic lesion area. Chromatin immunoprecipitation (ChIP) and luciferase reporter gene assays were used to confirm that KLF14 positively regulated miR-27a expression by binding to its promoter. We also found that KLF14 could restored appropriate cellular lipid homeostasis and inflammatory responses via negatively regulating lipoprotein lipase (LPL) expression in THP1-derived macrophages through miR-27a. In addition, gypenosides (GP), a KLF14 activator, delayed the development of atherosclerosis in apolipoprotein E deficient (apoE-/-) mice. CONCLUSIONS: KLF14 plays an antiatherogenic role via the miR-27a-dependent down-regulation of LPL and subsequent inhibition of proinflammatory cytokine secretion and lipid accumulation.

10.
Sheng Wu Yi Xue Gong Cheng Xue Za Zhi ; 36(4): 664-669, 2019 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-31441269

RESUMO

This study proposed a method to calibrate tube focus spot and the center plane of rotation in computed tomography system. In the method, the tube was rotated to 0° and 180° respectively, and then one metal jig with symmetric windows A and B was scanned at each position under the tube cool and static condition. According to the geometry of tube focus spot, aperture center of the collimator and jig, the distance between tube focus spot and the center plane of rotation were calculated with the X ray transmittance data after denoising, mean value and normalization. To verify the practicability and validity of the method, the tube focus spot in a 16 slices CT system (Brivo CT385, GE, China) was calibrated, and the result after calibration was validated by scanning a polaroid film. The validation result showed that the deviation between tube focal spot and center plane of rotation was 0.02 mm and was in the error range within ± 0.1 mm. The results of this study showed that, as a simple and low-cost design, the method could be used for fast calibration between tube focus spot and the center plane of rotation.


Assuntos
Rotação , Tomografia Computadorizada por Raios X , Calibragem , Raios X
11.
BMC Nephrol ; 20(1): 319, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412804

RESUMO

BACKGROUND: Chronic kidney disease (CKD) has been considered as a major health problem in the world. Increasing uric acid (UA) could induce vascular endothelial injury, which is closely related to microinflammation, oxidative stress, and disorders of lipids metabolism. However, the specific mechanism that UA induces vascular endothelial cells injury in early CKD remains unknown. METHODS: Human umbilical vein endothelial cells (HUVECs) were cultured and subjected to different concentrations of UA for different periods. Early CKD rat model with elevated serum UA was established. Western blotting and quantitative real-time PCR (qPCR) were applied for measuring protein and mRNA expression of different cytokines. The animals were sacrificed and blood samples were collected for measurement of creatinine, UA, IL-1ß, TNF-α, and ICAM-1. Renal tissues were pathologically examined by periodic acid-Schiff (PAS) or hematoxylin-eosin (HE) staining. RESULTS: The expression of IL-1ß, ICAM-1, NLRP3 complexes, and activation of NLRP3 inflammasome could be induced by UA, but the changes induced by UA were partially reversed by siRNA NLRP3 or caspase 1 inhibitor. Furthermore, we identified that UA regulated the activation of NLRP3 inflammasome by activating ROS and K+ efflux. In vivo results showed that UA caused the vascular endothelial injury by activating NLRP3/IL-1ß pathway. While allopurinol could reduce UA level and may have protective effects on cardiovascular system. CONCLUSIONS: UA could regulate NLRP3/IL-1ß signaling pathway through ROS activation and K+ efflux and further induce vascular endothelial cells injury in early stages of CKD.

12.
Artigo em Inglês | MEDLINE | ID: mdl-31452353

RESUMO

Block copolymer prodrugs (BCPs) have emerged as one of the most promising anticancer drug delivery strategies, which can self-assemble into nanoparticles with optimal physicochemical properties including sizes, morphologies, surface properties, and integration of multifunction for improved in vivo applications. Moreover, the utility of stimuli-responsive linkages to conjugate drugs onto the polymer backbones can achieve efficient and targeting drug release. Several BCP micellar delivery systems have been pushed ahead into the clinical trials, which showed great promising potentials for cancer therapy. In recent years, various novel and more efficient BCP systems have been developed for better in vivo performance. In this focus article, we focus on the recent advances of BCPs including the synthesis, self-assembly, and applications for cancer therapy. The synthetic methods are first introduced, and the self-assembly of BCPs for in vivo anticancer applications is discussed along the line of varying endogenous stimuli-responsive linkages including amide or ester bonds, pH, reduction, and oxidation-responsive linkages. Finally, conclusions along with the brief future perspectives are presented. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

13.
Int J Biol Macromol ; 140: 1249-1259, 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31465800

RESUMO

The therapeutics having ability to target cancer cells specifically and exhibit nominal cytopathic effect on normal healthy cells are highly significant for cancer therapeutic applications. Recombinant porcine natural killer lysin (rpNK-lysin) has proven cationic anti-bacterial and anti-tumor peptide. Herein, we report its anti-invasion and anti-metastasis effects on hepatocellular carcinoma (HCC) cells in vitro. We first investigate the maximum non-toxic concentration (MNTC) of rpNK-lysin for the normal hepato cells (L-02). Using MNTC rpNK-lysin, we explore anti-proliferative, anti-adhesive, anti-invasive and anti-metastatic effect of rpNK-lysin on three different HCC cells lines (SMMC-7721, 97-H and HepG2) through MTT, wound-healing, adhesion and invasion assay along with mRNA and protein expression. The results reveal that rpNK-lysin has potential to specifically inhibit HCC cells growth in a dose and time-dependent manner with a little cytopathic effect on the L-02 cells, effectively reduce migration, adhesion and invasion ability of HCC cells. rpNK-lysin significantly reduce Fascin1 expression, which subsequently decrease ß-catenin expression and metaloproteinases (MMP-2 and MMP9). This study suggest that MNTC rpNK-lysin has an anti-invasion and anti-metastasis effect on HCC cells in vitro through inhibition of Fascin 1 expression which regulates Wnt/ß-catenin signaling pathway by inducing ß-catenin degradation and subsequently results in suppression of MMP-2 and MMP9 expression.

14.
Chem Commun (Camb) ; 55(67): 10015-10018, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31378791

RESUMO

We report the first neutral and water-soluble polymer capable of strong mitochondrial targeting in vitro and in vivo, zwitterionic poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OPDEA). OPDEA is quickly internalized via macropinocytosis by various cancer cells and transferred into the mitochondria, which slightly lowers the mitochondrial membrane potential as determined by the JC-1 assay.


Assuntos
Mitocôndrias/metabolismo , Ácidos Polimetacrílicos/química , Animais , Linhagem Celular Tumoral , Corantes Fluorescentes/química , Humanos , Concentração de Íons de Hidrogênio , Potencial da Membrana Mitocondrial , Camundongos , Imagem Óptica/métodos , Permeabilidade , Ácidos Polimetacrílicos/metabolismo , Solubilidade , Água
15.
Cancer Res ; 79(19): 4951-4964, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31409639

RESUMO

Lysyl oxidase-like 2 (LOXL2), a copper-dependent enzyme of the lysyl oxidase family and its nonsecreted, catalytically dead spliced isoform L2Δ13, enhance cell migration and invasion, stimulate filopodia formation, modulate the expression of cytoskeletal genes, and promote tumor development and metastasis in vivo. We previously showed that LOXL2 reorganizes the actin cytoskeleton in esophageal squamous cell carcinoma (ESCC) cells, however, the underlying molecular mechanisms were not identified. Here, using interactome analysis, we identified ezrin (EZR), fascin (FSCN1), heat shock protein beta-1 (HSPB1), and tropomodulin-3 (TMOD3) as actin-binding proteins that associate with cytoplasmic LOXL2, as well as with its L2Δ13 variant. High levels of LOXL2 and L2Δ13 and their cytoskeletal partners correlated with poor clinical outcome in patients with ESCC. To better understand the significance of these interactions, we focused on the interaction of LOXL2 with ezrin. Phosphorylation of ezrin at T567 was greatly reduced following depletion of LOXL2 and was enhanced following LOXL2/L2Δ13 reexpression. Furthermore, LOXL2 depletion inhibited the ability of ezrin to promote tumor progression. These results suggest that LOXL2-induced ezrin phosphorylation, which also requires PKCα, is critical for LOXL2-induced cytoskeletal reorganization that subsequently promotes tumor cell invasion and metastasis in ESCC. In summary, we have characterized a novel molecular mechanism that mediates, in part, the protumorigenic activity of LOXL2. These findings may enable the future development of therapeutic agents targeting cytoplasmic LOXL2. SIGNIFICANCE: LOXL2 and its spliced isoform L2Δ13 promote cytoskeletal reorganization and invasion of esophageal cancer cells by interacting with cytoplasmic actin-binding proteins such as ezrin.

17.
Med Sci Monit ; 25: 5892-5902, 2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31391414

RESUMO

BACKGROUND Peritoneal dialysis is the most common treatment for end-stage renal disease. However, peritoneal fibrosis resulting from long-term peritoneal dialysis restricts peritoneal ultrafiltration. Previous studies have shown a role for 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) in preventing fibrosis, but the potential mechanisms remain unknown. This study aimed to investigate the role of 1,25(OH)2D3 in epithelial-mesenchymal transition (EMT) and the downstream signaling pathway in HMrSV5 human peritoneal mesothelial cells in vitro. MATERIAL AND METHODS An in vitro cell model of peritoneal fibrosis was established using the HMrSV5 human peritoneal mesothelial cell line. High glucose and lipopolysaccharide (LPS) culture conditions, with or without 1,25(OH)2D3, were used. Wnt agonist 1, a Wnt signaling pathway activator, was applied. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blot were used to measure the vitamin D receptor (VDR) and histone deacetylase 3 (HDAC3) gene and protein expression levels, ß-catenin, and EMT-associated biomarkers. RESULTS High glucose plus LPS culture medium inhibited cell proliferation, induced cell apoptosis and promoted EMT in HMrSV5 cells, which was reversed by 1,25(OH)2D3 by down-regulation of HDAC3 and upregulation of VDR. HDAC3 inhibited VDR gene expression. The expression of EMT-associated biomarkers was increased by Wnt agonist 1 and inhibited by 1,25(OH)2D3. CONCLUSIONS In HMrSV5 human peritoneal mesothelial cells, 1,25(OH)2D3 reversed EMT by inhibiting the expression of HDAC3 and upregulating VDR gene expression via the Wnt/ß-catenin signaling pathway.

18.
Biochem Soc Trans ; 47(4): 1101-1116, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31395755

RESUMO

The SRC, Abelson murine leukemia viral oncogene homolog 1, TEC and C-terminal SRC Kinase families of non-receptor tyrosine kinases (collectively the Src module kinases) mediate an array of cellular signaling processes and are therapeutic targets in many disease states. Crystal structures of Src modules kinases provide valuable insights into the regulatory mechanisms that control activation and generate a framework from which drug discovery can advance. The conformational ensembles visited by these multidomain kinases in solution are also key features of the regulatory machinery controlling catalytic activity. Measurement of dynamic motions within kinases substantially augments information derived from crystal structures. In this review, we focus on a body of work that has transformed our understanding of non-receptor tyrosine kinase regulation from a static view to one that incorporates how fluctuations in conformational ensembles and dynamic motions influence activation status. Regulatory dynamic networks are often shared across and between kinase families while specific dynamic behavior distinguishes unique regulatory mechanisms for select kinases. Moreover, intrinsically dynamic regions of kinases likely play important regulatory roles that have only been partially explored. Since there is clear precedence that kinase inhibitors can exploit specific dynamic features, continued efforts to define conformational ensembles and dynamic allostery will be key to combating drug resistance and devising alternate treatments for kinase-associated diseases.

19.
Chem Commun (Camb) ; 55(58): 8494-8497, 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31268095

RESUMO

A rational strategy was reported to construct boranil complexes (DPFB derivatives) with unique aggregation-induced emission effects by installing phenyl rings in the anil ligand as the intramolecular rotors. In view of the good biocompatibility and suitable lipophilicity, DPFB derivatives can serve as excellent fluorescent probes for specific imaging of lipid droplets in living cells and yolk lipids in zebrafish.


Assuntos
Compostos de Anilina/química , Compostos de Boro/química , Complexos de Coordenação/química , Corantes Fluorescentes/química , Gotículas Lipídicas/metabolismo , Compostos de Anilina/síntese química , Animais , Compostos de Boro/síntese química , Complexos de Coordenação/síntese química , Fluorescência , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Ligantes , Microscopia Confocal/métodos , Estrutura Molecular , Peixe-Zebra
20.
Vet Res ; 50(1): 53, 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300043

RESUMO

Our previous studies demonstrated that matrine directly acts on the replication process of porcine reproductive and respiratory syndrome virus (PRRSV). Matrine inhibits viral replication and is also associated with the NF-κB signalling pathway. These results suggest that matrine has antiviral and anti-inflammatory effects. However, the specific anti-inflammatory mechanism of matrine is still unclear. In this study, we investigated the anti-IL-1ß mechanism of matrine, as IL-1ß is a major inflammatory cytokine, in porcine alveolar macrophages (PAMs) stimulated with 4 µg PRRSV 5'-untranslated region (UTR) RNA and 1 µg/mL LPS. After 5'UTR RNA and LPS co-stimulation of PAMs for 12 h, the expression of IL-1ß, IL-6, IL-8 and TNF-α was significantly increased. The results also showed that co-stimulation induced the expression of MyD88, and activated the NF-κB signalling pathway and NLRP3 inflammasome. Furthermore, matrine treatment downregulated MyD88, NLRP3 and caspase-1 expression, inhibited ASC speck formation, suppressed IκBα phosphorylation, and interfered with the translocation of NF-κB from the cytoplasm to the nucleus. These results suggest that matrine plays an important role in PAMs co-stimulated with PRRSV 5'UTR RNA and LPS via its effect on NF-κB and the NLRP3 inflammasome. These findings lay the foundation for the exploration of the clinical application of matrine in PRRSV disease.

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