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1.
J Neuroinflammation ; 17(1): 97, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32238175

RESUMO

BACKGROUND: Activation of microglia and astrocytes, a prominent hallmark of both aging and Alzheimer's disease (AD), has been suggested to contribute to aging and AD progression, but the underlying cellular and molecular mechanisms are largely unknown. METHODS: We performed RNA-seq analyses on microglia and astrocytes freshly isolated from wild-type and APP-PS1 (AD) mouse brains at five time points to elucidate their age-related gene-expression profiles. RESULTS: Our results showed that from 4 months onward, a set of age-related genes in microglia and astrocytes exhibited consistent upregulation or downregulation (termed "age-up"/"age-down" genes) relative to their expression at the young-adult stage (2 months). And most age-up genes were more highly expressed in AD mice at the same time points. Bioinformatic analyses revealed that the age-up genes in microglia were associated with the inflammatory response, whereas these genes in astrocytes included widely recognized AD risk genes, genes associated with synaptic transmission or elimination, and peptidase-inhibitor genes. CONCLUSIONS: Overall, our RNA-seq data provide a valuable resource for future investigations into the roles of microglia and astrocytes in aging- and amyloid-ß-induced AD pathologies.

2.
Echocardiography ; 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32240547

RESUMO

OBJECTIVES: Right ventricular (RV) function is identified as a key determinant of the outcome in patients with pulmonary hypertension (PH). Several studies have assessed the role of peak global longitudinal RV strain in PH patients; however, less emphasis was given to the RV regional longitudinal strain. The aim of this study was to evaluate the regional RV systolic strain in PH patients and investigate the relationship of these parameters with the severity of PH. METHODS: RV regional longitudinal peak systolic strain (LPSS) and strain rate (LPSSR) were measured using speckle tracking echocardiography on 100 patients with PH who underwent right heart catheterization, and 29 control subjects. Severe PH was identified by a decreased cardiac index (CI) (<2.0 L/min/m2 ). RESULTS: LPSS and LPSSR of the RV free wall were significantly lower in PH patients than control subjects, especially when comparing the basal and mid regions (P < .001). When comparing severe PH and nonsevere PH, basal and mid LPSS and LPSSR were significantly lower (P < .001). RV free wall mid LPSSR correlated with CI (r = -.703, P < .001). In the multiple logistic regression analysis, mid LPSSR was identified as an independent predictor of severe PH (odds ratio 1.82; 95% confidential interval 1.39-2.40; P < .001). In the receiver operating characteristics curve analysis, a cutoff value of mid LPSSR of -0.92 s-1 predicted severe PH, with a sensitivity and specificity of 75.0% and 93.7%, respectively (AUC = 0.889, P < .001). CONCLUSIONS: RV free wall mid longitudinal peak systolic strain rate may be useful for the detection of severely impaired RV performance in PH.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32227981

RESUMO

Fullerenes have been recognized as good candidates for solid lubricants. In this study, the microscale superlubricity of fullerene derivatives was accomplished by the construction of regular host-guest assembly structures. Herein, the host-guest assembly structures of fullerene derivatives were successfully constructed on a highly oriented pyrolytic graphite (HOPG) surface by introducing the macrocycles as the templates and were explicitly revealed by scanning tunneling microscopy (STM). Meanwhile, the nanotribological properties of the host-guest assemblies were measured using atomic force microscopy (AFM), revealing ultralow friction coefficients of 0.003-0.008, which could be attributed to the restriction on removal of fullerene molecules after introducing the templates. The interaction energies were calculated by density functional theory (DFT) method, which indicates the correlation between friction coefficients and interaction strength in the host-guest assemblies. The effort on fullerene-related superlubricity could extend the solid superlubrication systems and provide a novel pathway to explore the friction mechanisms at the molecular level.

4.
ACS Chem Biol ; 2020 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-32243127

RESUMO

Glioblastoma multiforme (GBM) is an incurable disease. Like most solid tumors, GBM harbors multiple overexpressed and mutated genes. Small molecules that selectively modulate these targets and their signaling pathways are expected to inhibit GBM phenotypes without affecting normal non-transformed cells. Phenotypic screening can be an effective strategy to uncover such compounds, but a significant limitation is the need for large and diverse libraries to enable the efficient exploration of the large number of cellular targets. Here, we create small chemical libraries by structure-based molecular docking large libraries to a collection of GBM-specific targets identified using the tumor's RNA-seq and mutation data along with cellular protein-protein interaction data. Screening of this enriched library of 50 candidates led to several active compounds. Among them 1 (IPR-2025), which (i) inhibited cell viability of low-passage patient-derived GBM spheroids with single-digit micromolar IC50s that are substantially better than standard-of-care temozolomide; (ii) blocked tube-formation of endothelial cells in Matrigel with sub-micromolar IC50s; and (iii) had no effect on primary hematopoietic CD34+ progenitor spheroids or astrocyte cell viability. RNA sequencing (RNA-seq) provided potential mechanism of action of 1 and mass spectrometry-based thermal proteome profiling (TPP) revealed possible targets that included the scaffold protein RACK1, which was among targets predicted by molecular docking. The ability of 1 to inhibit GBM phenotypes without affecting normal cell viability suggests that our screening approach that consists of creating enriched libraries by focusing on the tumor's genomic profile may hold promise for generating lead compounds with a high therapeutic index for treatments of incurable diseases like GBM.

5.
Int J Mol Med ; 2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-32236583

RESUMO

Osteosarcoma (OS) is one of the most common malignant tumors in young adults and has a high distant metastasis rate. The p53 protein, a potent prognostic biomarker for patients with OS, is altered in ~50% of OS cases. p53 was reported to exert its effects through regulating the transcription of microRNAs (miRNAs/miRs) and other genes. In the present study, the expression of miR­181b, a critical OS oncomiR, was shown to be significantly upregulated whereas p53 expression was downregulated within OS tissues and cells; in tissue samples, miR­181b and p53 were negatively correlated. p53 inhibited the transcription of miR­181b via targeting its promoter region, whereas miR­181b bound the TP53 3'­untranslated region (UTR) to inhibit p53 expression. miR­181b silencing considerably increased p53, p21, and epithelial­Cadherin protein levels but decreased Cyclin D1 protein levels in OS cells. In addition, miR­181b inhibition reduced OS cell proliferation and invasion. In contrast, p53 knockdown had the opposite effects on these proteins and OS cell proliferation and invasion. Above all, p53 knockdown significantly attenuated the effects of miR­181b inhibition. Moreover, OS cell xenograft assays further confirmed the roles of the miR­181b/p53 axis in OS growth. In conclusion, miR­181b and p53 are negatively regulated by one another and therefore form a negative feedback axis that regulates the proliferation and invasion abilities of OS cells. Targeting miR­181b to inhibit its abnormal upregulation might be a potent strategy for OS treatment.

6.
Stem Cells Dev ; 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32122266

RESUMO

To remedy the lack of human leukocyte antigen (HLA)-matched donors and address the problems bedeviling traditional allogeneic hematopoietic stem cell transplantation which induces the resultant graft-versus-host disease, we designed a scheme called HLA-mismatched hematopoietic stem cell microtransplantation (MST) for patients with acute myeloid leukemia (AML), where encouraging results were achieved. In providing answers to such questions as how to select the donors of MST and which factors were involved in the outcome of MST. One hundred thirty-one AML patients from four centers with lower or standard risk of prognosis after complete remission were given three courses of MST: high dose of cytarabine plus infusion of granulocyte colony-stimulating factor mobilized peripheral blood stem cells from HLA-mismatched donors. Leukemia-free survival (LFS) and overall survival were compared, with respect to gender difference, number of HLA-matched loci, killer cell immunoglobulin-like receptor (KIR), and ligand mismatch between donors and recipients. Median LFS of recipients with different KIR ligands from those of donors was found to be significantly higher than that of recipients having identical ligands with donors (P < 0.05). The mean LFS was statistically different between recipients whose donors had HLA-C1/C2 ligand and those whose donors had C1/C1 or C2/C2 ligand (P < 0.05). The following factors were found to promote long-term survival: female recipients of male donors' stem cell, and donors with different KIR ligands from recipients.

7.
Br J Nutr ; : 1-32, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32213215

RESUMO

Previous studies have shown conflicting findings regarding the relationship between maternal vitamin D deficiency (VDD) and foetal growth restriction (FGR). We hypothesized that parathyroid hormone (PTH) may be an underlying factor relevant to this potential association. In a prospective birth cohort study, descriptive statistics were evaluated for the demographic characteristics of 3407 pregnancies in the second trimester from three antenatal clinics in Hefei, China. The association of the combined status of VD and PTH with birth weight and the risk of small for gestational age (SGA) was assessed by a multivariate linear and binary logistic regression. We found that declined status of 25(OH) D are associated with the lower birth weight (for moderate VDD : adjusted ß=-49.4 g, 95% CI: -91.1, -7.8, P <0.05; for severe VDD: adjusted ß=-79.8 g, 95% CI: -127.2, -32.5, P <0.01), as well as ascended levels of PTH (for elevated PTH: adjusted ß=-44.5 g, 95% CI: -82.6, -6.4, P <0.05). Compared to the non-VDD group with non-elevated PTH, pregnancies with severe VDD and elevated PTH had the lowest neonatal birthweight (adjusted ß=-124.7 g, 95% CI: -194.6, -54.8, P <0.001) and the highest risk of SGA (adjusted RR=3.36, 95% CI: 1.41, 8.03, P <0.01). Notably, the highest risk of less calcium supplementation were founded in severe VDD group with elevated PTH (adjusted RR=4.67, 95% CI: 2.78, 7.85, P <0.001).In conclusion, elevated PTH induced by less calcium supplementation would further aggravate the risk of FGR in pregnancies with severe VDD through impaired maternal calcium metabolism homeostasis.

9.
Anatol J Cardiol ; 23(3): 151-159, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32120360

RESUMO

OBJECTIVE: Interleukin (IL) 25, also known as IL-17E, is an inflammatory cytokine and has been demonstrated to be closely related to cardiovascular diseases by regulating immunity and inflammation, including atherosclerosis. This study was aimed to evaluate the expression of IL-25 in patients with coronary artery disease (CAD). METHODS: In this study, the expression of IL-25 in normal (n=6) and atherosclerotic (n=10) human coronary arteries was detected by immunofluorescent staining. In addition, the serum IL-25, IL-6, and tumor necrosis factor (TNF) α concentrations in stable angina pectoris (SAP, n=44), unstable angina pectoris (UAP, n=46), acute myocardial infarction (AMI, n=34), and non-CAD (control, n=36) were measured using enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: IL-25 was significantly increased in coronary arteries of CAD patients when compared with normal coronary arteries, with macrophages and T lymphocytes being the sources of IL-25, especially macrophages. Moreover, the serum concentrations of IL-25 were markedly elevated in CAD patients and gradually increased in SAP, UAP, and AMI groups. In addition, IL-25 levels were positively correlated with the IL-6 and TNF-α levels, and Gensini score in CAD patients. Logistic regression analysis showed that IL-25 was independently positively correlated with the occurrence of acute coronary syndrome (ACS). A receiver operator characteristic curve suggested that IL-25 presented a significant diagnosis value in ACS. CONCLUSION: IL-25 is increased in the coronary arteries and serum of CAD patients and is associated with the severity of coronary stenosis and the occurrence of ACS, suggesting that IL-25 may be one of the biomarkers of ACS.

10.
J Pathol Clin Res ; 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32149481

RESUMO

Myeloid-derived suppressor cells with polymorphonuclear morphology (PMN-MDSCs) contribute to the progression and immune evasion of prostate cancer. However, the spatial distribution of tumor-infiltrating PMN-MDSCs in primary and metastatic prostate cancer, especially in the context of comparison between the epithelial and stromal compartments of the tumor, has not been characterized. Here, we describe a multicolor immunofluorescence staining study of 90 primary tumors, 37 lymph node metastases (all with matched primary tumors) and 35 bone metastases using archived samples. CD11b+ CD15+ cells were identified as PMN-MDSCs and pan-cytokeratin+ cells were identified as prostate epithelial cells. We found that, in both primary tumor and metastases, PMN-MDSCs infiltrate much more readily in the stromal area compared with the epithelial area of the tumor regions. In comparison to the stromal area of primary tumors, the stromal area of either lymph node metastases or bone metastases was infiltrated with more PMN-MDSCs. In primary tumors, stromal PMN-MDSCs were associated with vascularization, segmented neutrophils, patient age and close juxtaposition to neoplastic epithelial cells. These results reveal the stroma rather than the epithelia of prostate cancer as the major hotbed for PMN-MDSCs and support the role of PMN-MDSCs in the metastatic progression of prostate cancer.

11.
Fish Shellfish Immunol ; 99: 572-577, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32112890

RESUMO

The pleiotropic transcription factor nuclear factor-kappa B (NF-κB) has important functions in viral resistance. In the present study, we isolated a p65 subunit of NF-κB cDNA from Pelteobagrus vachellii (termed Pvp65) and characterized it. The full-length p65 cDNA comprised 3651 bp, including a 148-bp 5'-untranslated region (UTR), a 106-bp 3'-UTR, and an open reading frame encoding a 1067-amino acid putative protein. The protein sequence comprised a DNA binding motif, a Rel-homology domain, a Rel protein signature, a putative transcription activation domain, a nuclear localization signal, and a transcription initiation factor IIA domain. The expression of Pvp65 displayed a daily rhythm, with an acrophase at approximately at 15:32 h in the liver, 11:34 h in the spleen, and 16:45 h in the head kidney. In addition, infection with Aeromonas hydrophila caused Pvp65 expression to increase significantly (P < 0.05), and peaking at 12 h post infection in the spleen, at 24 in the head kidney, and at 12 h in the liver. Thus, NF-κB expression might be under light/dark cycle control in P. vachellii, and may be involved in the immune response to A. hydrophila.

12.
Exp Cell Res ; : 111941, 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32145252

RESUMO

BACKGROUND: Endothelial-to-mesenchymal transition (EndMT) has been implicated in initiation and progression of pulmonary arterial hypertension (PAH). Gremlin-1 promotes vascular remodeling of PAH and mediates epithelial-mesenchymal transition, which is similar to EndMT. In the present study we investigated the potential role of gremlin-1 plays in EndMT of pulmonary artery endothelial cells (PAECs). METHODS: Immunofluorescence staining was performed to detect the expression of alpha smooth muscle actin (α-SMA) and von Willebrand factor (VWF). Migration and angiogenic responses of PAECs were determined by transwell assay and tube formation assay, respectively. Protein expression levels were determined by western blotting. RESULTS: Gremlin-1 induced EndMT of PAECs in a phospho-smad2/3-dependent manner. This was characterized by the loss of platelet endothelial cell adhesion molecule 1 and an increase in protein levels of a-SMA, nerve-cadherin, and matrix metalloproteinase 2. It was also determined that gremlin-1 facilitated the migration and angiogenic responses of PAECs in a dose-dependent manner. Bone morphogenetic protein 7 (BMP-7) was found to attenuate gremlin-1-mediated EndMT, migration and angiogenesis of PAECs by inducing phosphorylation of Smad1/5/8 and suppressing phosphorylation of Smad2/3. CONCLUSION: Gremlin-1 mediates EndMT in PAECs, and BMP-7 reverses gremlin-1-induced EndMT by an induction of p-Smad1/5/8 and suppression of p-Smad2/3.

13.
Food Chem ; 318: 126518, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32151925

RESUMO

Cocoa butter substitutes (CBS) used for chocolate preparation was produced using a mixture of palm kernel oil (PKO) and enzymatically interesterified fats. The interesterified fats consisted of palm olein (POL), fully hydrogenated palm oil (FHPO) and PKO that were catalyzed using Lipozyme TL IM at 65 °C in a solvent-free packed bed reactor. An interesterification degree of 97.10% was obtained using feed flow rate of 70 mL/min and the interesterified fats showed steep solid fat content (SFC) curve characteristics with low SFC at high temperature. In the binary system, PKO and the interesterified fats showed good compatibility at 5-10 °C, while eutectic effects were observed at 15-35 °C. CBS produced from PKO and the interesterified fats in a mass ratio of 4:6 (CBS-46) and 3:7 (CBS-37) had crystals formed prominently in the ß' form. Without the need of a tempering process, chocolate made using CBS-46 as the base oil exhibited the desired properties in terms of hardness and fracturability.

14.
Insects ; 11(3)2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32197450

RESUMO

Transient receptor potential (TRP) channels are critical for insects to detect environmental stimuli and regulate homeostasis. Moreover, this superfamily has become potential molecular targets for insecticides or repellents. Pieris rapae is one of the most common and widely spread pests of Brassicaceae plants. Therefore, it is necessary to study TRP channels (TRPs) in P. rapae. In this study, we identified 14 TRPs in P. rapae, including two Water witch (Wtrw) genes. By contrast, only one Wtrw gene exists in Drosophila and functions in hygrosensation. We also found splice isoforms of Pyrexia (Pyx), TRPgamma (TRPγ) and TRP-Melastatin (TRPM). These three genes are related to temperature and gravity sensation, fine motor control, homeostasis regulation of Mg2+ and Zn2+ in Drosophila, respectively. Evolutionary analysis showed that the TRPs of P. rapae were well clustered into their own subfamilies. Real-time quantitative PCR (qPCR) showed that PrTRPs were widely distributed in the external sensory organs, including antennae, mouthparts, legs, wings and in the internal physiological organs, including brains, fat bodies, guts, Malpighian tubules, ovaries, as well as testis. Our study established a solid foundation for functional studies of TRP channels in P. rapae, and would be benefit to developing new approaches to control P. rapae targeting these important ion channels.

15.
Food Res Int ; 130: 108908, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32156355

RESUMO

Longjing tea is the most famous premium green tea, and is regarded as the national tea in China, with its attractive aroma contributing as a prime factor for its general acceptability; however, its key aroma compounds are essentially unknown. In the present study, volatile compounds from Longjing tea were extracted and examined using stir bar sorptive extraction (SBSE) combined with gas chromatography-mass spectrometry (GC-MS). Data obtained from the present study revealed that 151 volatile compounds from 16 different chemical classes were identified by GC-MS analysis. Enols (8096 µg/kg), alkanes (6744 µg/kg), aldehydes (6442 µg/kg), and esters (6161 µg/kg) were the four major chemical classes and accounted for 54% of the total content of volatile compounds. Geraniol (6736 µg/kg) was the most abundant volatile compound in Longjing tea, followed by hexanal (1876 µg/kg) and ß-ionone (1837 µg/kg). Moreover, 14 volatile compounds were distinguished as the key aroma compounds of Longjing tea based on gas chromatography-olfactometry (GC-O) analysis, odor activity value (OAV) calculations, and a preliminary aroma recombination experiment, including 2-methyl butyraldehyde, dimethyl sulfoxide, heptanal, benzaldehyde, 1-octen-3-ol, (E, E)-2,4-heptadienal, benzeneacetaldehyde, linalool oxide I, (E, E)-3,5-octadien-2-one, linalool, nonanal, methyl salicylate, geraniol, and ß-ionone. This is the first comprehensive report describing the aroma characterizations and the key aroma compounds in Longjing tea using SBSE/GC-MS. The findings from this study contribute to the scientific elucidation of the chemical basis for the aromatic qualities of Longjing tea.

16.
Eur Radiol ; 2020 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-32064559

RESUMO

OBJECTIVES: To take advantage of the deep learning algorithms to detect and calculate clot burden of acute pulmonary embolism (APE) on computed tomographic pulmonary angiography (CTPA). MATERIALS AND METHODS: The training set in this retrospective study consisted of 590 patients (460 with APE and 130 without APE) who underwent CTPA. A fully deep learning convolutional neural network (DL-CNN), called U-Net, was trained for the segmentation of clot. Additionally, an in-house validation set consisted of 288 patients (186 with APE and 102 without APE). In this study, we set different probability thresholds to test the performance of U-Net for the clot detection and selected sensitivity, specificity, and area under the curve (AUC) as the metrics of performance evaluation. Furthermore, we investigated the relationship between the clot burden assessed by the Qanadli score, Mastora score, and other imaging parameters on CTPA and the clot burden calculated by the DL-CNN model. RESULTS: There was no statistically significant difference in AUCs with the different probability thresholds. When the probability threshold for segmentation was 0.1, the sensitivity and specificity of U-Net in detecting clot respectively were 94.6% and 76.5% while the AUC was 0.926 (95% CI 0.884-0.968). Moreover, this study displayed that the clot burden measured with U-Net was significantly correlated with the Qanadli score (r = 0.819, p < 0.001), Mastora score (r = 0.874, p < 0.001), and right ventricular functional parameters on CTPA. CONCLUSIONS: DL-CNN achieved a high AUC for the detection of pulmonary emboli and can be applied to quantitatively calculate the clot burden of APE patients, which may contribute to reducing the workloads of clinicians. KEY POINTS: • Deep learning can detect APE with a good performance and efficiently calculate the clot burden to reduce the physicians' workload. • Clot burden measured with deep learning highly correlates with Qanadli and Mastora scores of CTPA. • Clot burden measured with deep learning correlates with parameters of right ventricular function on CTPA.

17.
J Thromb Haemost ; 2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32108990

RESUMO

BACKGROUND: Fluorogenic thrombin generation (TG) assays are commonly used to determine global coagulation phenotype in plasma. Whole blood (WB)-TG assays reach one step closer to physiology by involving the intrinsic blood cells, but erythrocytes cause variable quenching of the fluorescence signals, hampering its routine application. OBJECTIVE: To develop a new assay for continuous WB-TG measurement. METHODS: In the new WB-TG assay, the erythrocyte-caused distortion of signal was solved by continuously mixing the sample during the measurement. The assay was validated by evaluating the reproducibility and comparing with the paper-based WB-TG assay. Reconstituted human blood and WB from 119 healthy donors was tested to explore the influences of hematocrit and platelet count on TG. RESULTS: This novel WB-TG assay showed good reproducibility while being less affected by contact activation compared with the previous paper-based assay. Reconstitution experiments showed that the lag time of TG was shortened by the addition of platelets but not erythrocytes. Increasing hematocrit strongly augmented the peak thrombin, even in the presence of high platelet counts. The lag time and peak of WB-TG of 119 healthy donors were positively related to erythrocyte count after adjusting for age, sex, and oral contraceptive use with multiple linear regression analyses. The reference range and interindividual variation of WB-TG were determined in the healthy cohort. CONCLUSIONS: A novel WB-TG assay was developed, which is a straightforward tool to measure the involvement of platelets and erythrocytes in TG and may assist the research of blood cell-associated coagulation disorders.

18.
Cell Chem Biol ; 27(3): 350-362.e8, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32017920

RESUMO

Polo-like kinase 1 has hundreds of substrates and multiple functions that operate within the ∼60 min of mitosis. Herein, we describe a chemical-genetic system that allows particular substrates to be "toggled" into or out of chemical control using engineered phosphoacceptor selectivity. Biochemical assays and phosphoproteomic analysis of mitotic cell extracts showed that Plk1S (L197F) and Plk1T (L197S/L211A) selectively phosphorylate Ser and Thr, respectively. Plk1S but not Plk1T sustains mitotic progression to anaphase, affording the opportunity to toggle substrate residues between Ser and Thr to place them under chemical control. Using this system, we evaluated Kif2b, a known substrate of Plk1 that regulates chromosome alignment. Toggling Ser to Thr on Kif2b places these phosphorylation sites under reversible chemical control, as indicated by a sharp increase in the frequency of misaligned chromosomes and prometaphase arrest. Thus, we demonstrate the ability to chemically control a single substrate by a genetic Ser/Thr toggle.

19.
EMBO Rep ; 21(3): e48692, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32072744

RESUMO

Dysregulation of lipid homeostasis is intimately associated with defects in insulin secretion, a key feature of type 2 diabetes. Here, we explore the role of the putative lipid transporter ABCA12 in regulating insulin secretion from ß-cells. Mice with ß-cell-specific deletion of Abca12 display impaired glucose-stimulated insulin secretion and eventual islet inflammation and ß-cell death. ABCA12's action in the pancreas is independent of changes in the abundance of two other cholesterol transporters, ABCA1 and ABCG1, or of changes in cellular cholesterol or ceramide content. Instead, loss of ABCA12 results in defects in the genesis and fusion of insulin secretory granules and increases in the abundance of lipid rafts at the cell membrane. These changes are associated with dysregulation of the small GTPase CDC42 and with decreased actin polymerisation. Our findings establish a new, pleiotropic role for ABCA12 in regulating pancreatic lipid homeostasis and insulin secretion.

20.
Cancer Manag Res ; 12: 1229-1240, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32110097

RESUMO

Background: As a key subtype of non-coding RNAs, circular RNA (circRNA) has been well documented to play a key role in the tumorigenesis of osteosarcoma (OS). circPVT1 was revealed to participate in the progression of multiple human tumors; however, the roles of circPVT1 in OS invasion and metastasis and its potential mechanisms remain elusive. Methods: RNA expression in OS tissues and cells was examined by qRT-PCR, protein expression was measured by Western blot. circPVT1 knockdown in vitro was achieved by transfecting OS cells with specific siRNAs. OS cell proliferation was assessed via CCK-8 and colony formation assays. OS cell migration and invasion were evaluated by transwell assay. Interaction between miR-205-5p and circPVT1 or c-FLIP was validated through dual-luciferase reporter assay. Rescue experiments were performed to explore the regulatory net among circPVT1, miR-205-5p and c-FLIP in OS progression in vitro. Results: circPVT1 and c-FLIP were highly expressed, while miR-205-5p was lowly expressed in OS tissues and cell lines. Knockdown of circPVT1 repressed cell proliferation, migration and invasion via inhibiting epithelial-mesenchymal transition (EMT) in OS. circPVT1 functioned as a sponge of miR-205-5p, and c-FLIP was targeted by miR-205-5p in OS cells. Furthermore, circPVT1 indirectly regulated c-FLIP expression through competitively binding to miR-205-5p. Inhibition of miR-205-5p or overexpression of c-FLIP abolished the effects of si-circPVT1 on cell proliferation, migration and invasion. Conclusion: Our study demonstrated circPVT1 functions as a sponge for miR-205-5p to promote c-FLIP expression, thereby enhancing EMT and inducing OS invasion and metastasis in vitro, implying that circPVT1 might be a potential therapeutic target for further clinical therapy of OS.

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