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1.
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.

2.
Cell Transplant ; 28(8): 1062-1070, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31198047

RESUMO

Intravoxel incoherent motion has received extensive attention in brain studies for its potential as a non-invasive magnetic resonance perfusion method. However, studies on intravoxel incoherent motion imaging and crossed cerebellar diaschisis detection are relatively scarce. The aim of our study was to evaluate the feasibility of using intravoxel incoherent motion imaging in crossed cerebellar diaschisis diagnosis in subacute ischemic stroke patients by comparing results from intravoxel incoherent motion imaging, single-photon emission computed tomography, and arterial spin-labeling perfusion methods. In total, 39 patients with subacute ischemic stroke who underwent intravoxel incoherent motion, arterial spin-labeling, and single-photon emission computed tomography scanning were enrolled. Intravoxel incoherent motion-derived perfusion-related parameters including fast diffusion coefficient, vascular volume fraction, arterial spin-labeling-derived cerebral blood flow as well as single-photon emission computed tomography-derived cerebral blood flow of bilateral cerebellum were measured. A crossed cerebellar diaschisis-positive result was considered present with an asymmetry index ≥10% of single-photon emission computed tomography. In the crossed cerebellar diaschisis-positive group, fast diffusion coefficient, arterial spin-labeling-derived cerebral blood flow, and computed tomography-derived cerebral blood flow of the contralateral cerebellum decreased compared with those of the ipsilesional cerebellum; whereas vascular volume fraction significantly increased. The National Institutes of Health Stroke Scale score and infarct volume in the crossed cerebellar diaschisis-positive group were significantly higher than those in the crossed cerebellar diaschisis-negative group. A positive correlation was detected between the fast diffusion coefficient-based asymmetry index and the single-photon emission computed tomography-based asymmetry index, fast diffusion coefficient-based asymmetry, and arterial spin-labeling based asymmetry index; whereas the vascular volume fraction-based asymmetry index value had a negative correlation with the single-photon emission computed tomography-based asymmetry index and arterial spin-labeling based asymmetry index. Furthermore, the area under the receiver operating characteristic curve value of the arterial spin-labeling-based asymmetry index was 0.923. The fast diffusion coefficient derived from the intravoxel incoherent motion could be valuable for the assessment of crossed cerebellar diaschisis in supratentorial stroke patients.

3.
Org Biomol Chem ; 17(25): 6201-6214, 2019 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-31179474

RESUMO

We have recently reported computational models for prediction of cell-based anticancer activity using machine learning methods. Herein, we have developed an integrated strategy to discover new anticancer agents using a cascade of the established screening models. Application of this strategy identified 17 compounds with antitumor activity. Among these compounds, h2 (containing a pyrazolo[3,4-b]pyridin-6-one scaffold) exhibited anticancer activity against six tumor cell lines, including MDA-MB-231, HeLa, MCF-7, HepG2, CNE2 and HCT116, with IC50 values of 13.37, 13.04, 15.45, 7.05, 9.30 and 8.93 µM. Subsequently, a total of 61 h2 analogues were obtained by similarity searching and tested for their anticancer activities. I2 was identified as a novel anticancer agent having activity against MDA-MB-231, HeLa, MCF-7, HepG2, CNE2 and HCT116 tumor cell lines with IC50 values of 3.30, 5.04, 5.08, 3.71, 2.99 and 5.72 µM. I2 also showed potent cytotoxicity against adriamycin-resistant human breast and hepatocarcinoma cells. Further investigation revealed that I2 inhibited the microtubule polymerization by binding to the colchicine site, resulting in inhibition of cell migration, cell cycle arrest in the G2/M phase and apoptosis of cancer cells. Finally, molecular docking and molecular dynamics provided insights into the binding interactions of I2 with tubulin. This study identified I2 as a novel starting point for further development of anticancer agents that target tubulin.

4.
Zhongguo Yi Liao Qi Xie Za Zhi ; 43(3): 226-229, 2019 May 30.
Artigo em Chinês | MEDLINE | ID: mdl-31184086

RESUMO

The artificial intelligence based on medical aid diagnosis has been in full swing in these years. How to better and more safely utilize this new technology to improve the diagnostic efficiency and quality of doctors poses new challenges for our hospital management. This paper aims to explore relevant management problems and corresponding solutions from seven aspects:data security, system integration, technical parameters, risks, workflows and diagnosis results by introducing a new intelligent image screening system. After these management problems have been better solved, we found that the intelligent image screening system can improve the diagnostic efficiency and quality of doctors.


Assuntos
Inteligência Artificial , Administração Hospitalar
5.
Gut ; 68(12): 2214-2227, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31171625

RESUMO

OBJECTIVE: Although glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-ß superfamily, its function in liver fibrosis has rarely been studied. Here, we investigated the role of GDNF in hepatic stellate cell (HSC) activation and liver fibrosis in humans and mice. DESIGN: GDNF expression was examined in liver biopsies and sera from patients with liver fibrosis. The functional role of GDNF in liver fibrosis was examined in mice with adenoviral delivery of the GDNF gene, GDNF sgRNA CRISPR/Cas9 and the administration of GDNF-blocking antibodies. GDNF was examined on HSC activation using human and mouse primary HSCs. The binding of activin receptor-like kinase 5 (ALK5) to GDNF was determined using surface plasmon resonance (SPR), molecular docking, mutagenesis and co-immunoprecipitation. RESULTS: GDNF mRNA and protein levels are significantly upregulated in patients with stage F4 fibrosis. Serum GDNF content correlates positively with α-smooth muscle actin (α-SMA) and Col1A1 mRNA in human fibrotic livers. Mice with overexpressed GDNF display aggravated liver fibrosis, while mice with silenced GDNF expression or signalling inhibition by GDNF-blocking antibodies have reduced fibrosis and HSC activation. GDNF is confined mainly to HSCs and contributes to HSC activation through ALK5 at His39 and Asp76 and through downstream signalling via Smad2/3, but not through GDNF family receptor alpha-1 (GFRα1). GDNF, ALK5 and α-SMA colocalise in human and mouse HSCs, as demonstrated by confocal microscopy. CONCLUSIONS: GDNF promotes HSC activation and liver fibrosis through ALK5/Smad signalling. Inhibition of GDNF could be a novel therapeutic strategy to combat liver fibrosis.

6.
J Med Chem ; 62(11): 5370-5381, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31082234

RESUMO

Targeting RANKL/RANK offers the possibility of developing novel therapeutic approaches to treat bone metabolic diseases. Multiple efforts have been made to inhibit RANKL. For example, marketed monoclonal antibody drug Denosumab could inhibit the maturation of osteoclasts by binding to RANKL. This study is an original approach aimed at discovering small-molecule inhibitors impeding RANKL/RANK protein interaction. We identified compound 34 as a potent and selective RANKL/RANK inhibitor by performing structure-based virtual screening and hit optimization. Disruption of the RANKL/RANK interaction by 34 effectively inhibits RANKL-induced osteoclastogenesis and bone resorption. The expression of osteoclast marker genes was also suppressed by treatment of 34. Furthermore, 34 markedly blocked the NFATc1/c-fos pathway. Thus, our current work demonstrates that the chemical tractability of the difficult PPI (RANKL/RANK) target by a small-molecule compound 34 offers a potential lead compound to facilitate the development of new medications for bone-related diseases.

7.
J Biomed Nanotechnol ; 15(6): 1162-1171, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31072425

RESUMO

The development of functional contrast agents for diagnosis and therapy of functional gastrointestinal disorders has been a focus of research in recent years. Owing to the excellent distribution and function of 5-HT3 in gastrointestinal mucosa, a novel magnetic contrast agent (AH-CTS-Gd nanosphere) was prepared based on chitosan and 5-HT3 receptors, which realize multifunctional assessment of gastric emptying and gastrointestinal mucosa-targeted MR imaging. The obtained AH-CTS-Gd nanosphere was administered orally to avoid potential toxicity from intravenous administration of a high dose. The results showed that a suitable gastric emptying time and clear gastrointestinal mucosa structure can be observed using the obtained AH-CTS-Gd nanosphere. Immunofluorescence and TEM images of gastrointestinal mucosa suggested a strong combination of the AH-CTS-Gd nanosphere with gastrointestinal mucosa because chitosan and Anti-5-HT3R can combine with gastrointestinal mucosa through electrostatic adherence and antigen-antibody binding. This technology has potential applications in the examination of functional gastrointestinal diseases, without affecting the detection of gastric emptying, possibly enhancing mucosal imaging.


Assuntos
Meios de Contraste/administração & dosagem , Administração Oral , Quitosana , Imagem por Ressonância Magnética , Magnetismo , Membrana Mucosa
8.
Korean J Radiol ; 20(5): 791-800, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30993930

RESUMO

OBJECTIVE: To compare various models of diffusion-weighted imaging including monoexponential apparent diffusion coefficient (ADC), biexponential (fast diffusion coefficient [Df], slow diffusion coefficient [Ds], and fraction of fast diffusion), stretched-exponential (distributed diffusion coefficient and anomalous exponent term [α]), and kurtosis (mean diffusivity and mean kurtosis [MK]) models in the differentiation of renal solid masses. MATERIALS AND METHODS: A total of 81 patients (56 men and 25 women; mean age, 57 years; age range, 30-69 years) with 18 benign and 63 malignant lesions were imaged using 3T diffusion-weighted MRI. Diffusion model selection was investigated in each lesion using the Akaike information criteria. Mann-Whitney U test and receiver operating characteristic (ROC) analysis were used for statistical evaluations. RESULTS: Goodness-of-fit analysis showed that the stretched-exponential model had the highest voxel percentages in benign and malignant lesions (90.7% and 51.4%, respectively). ADC, Ds, and MK showed significant differences between benign and malignant lesions (p < 0.05) and between low- and high-grade clear cell renal cell carcinoma (ccRCC) (p < 0.05). α was significantly lower in the benign group than in the malignant group (p < 0.05). All diffusion measures showed significant differences between ccRCC and non-ccRCC (p < 0.05) except Df and α (p = 0.143 and 0.112, respectively). α showed the highest diagnostic accuracy in differentiating benign and malignant lesions with an area under the ROC curve of 0.923, but none of the parameters from these advanced models revealed significantly better performance over ADC in discriminating subtypes or grades of renal cell carcinoma (RCC) (p > 0.05). CONCLUSION: Compared with conventional diffusion parameters, α may provide additional information for differentiating benign and malignant renal masses, while ADC remains the most valuable parameter for differentiation of RCC subtypes and for ccRCC grading.

9.
FASEB J ; 33(5): 6622-6631, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30794430

RESUMO

M1 muscarinic acetylcholine receptors are highly expressed in key areas that control cognition, such as the cortex and hippocampus, representing one potential therapeutic target for cognitive dysfunctions of Alzheimer's disease and schizophrenia. We have reported that M1 receptors facilitate cognition by promoting membrane insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor AMPA receptor subunit 1 (GluA1) through phosphorylation at Ser845. However, the signaling pathway is still unclear. Here we showed that adenylyl cyclase inhibitor 2',5'-dideoxyadenosine and PKA inhibitor KT5720 inhibited enhancement of phosphorylation of Ser845 and membrane insertion of GluA1 induced by M1 receptor activation. Furthermore, PI3K inhibitor LY294002 and protein kinase B (Akt) inhibitor IV blocked the effects of M1 receptors as well. Remarkably, the increase of the activity of PI3K-Akt signaling induced by M1 receptor activation could be abolished by cAMP-PKA inhibitors. Moreover, inhibiting the mammalian target of rapamycin (mTOR) complex 1, an important downstream effector of PI3K-Akt, by short-term application of rapamycin attenuated the effects of M1 receptors on GluA1. Furthermore, such effect was unrelated to possible protein synthesis promoted by mTOR. Taken together, these data demonstrate that M1 receptor activation induces membrane insertion of GluA1 via a signaling linking cAMP-PKA and PI3K-Akt-mTOR pathways but is irrelevant to protein synthesis.-Zhao, L.-X., Ge, Y.-H., Li, J.-B., Xiong, C.-H., Law, P.-Y., Xu, J.-R., Qiu, Y., Chen, H.-Z. M1 muscarinic receptors regulate the phosphorylation of AMPA receptor subunit GluA1 via a signaling pathway linking cAMP-PKA and PI3K-Akt.

10.
Sci Rep ; 9(1): 2644, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30804397

RESUMO

The association between global and segmental myocardial strain impairment and fibrosis extent in hypertrophic cardiomyopathy (HCM) is widely verified. The aim of this study was to investigate the contribution of high T2-weighted signal intensity (HighT2) to myocardial deformation in HCM. We prospectively recruited 57 patients with HCM examined by a 3.0 Tesla magnetic resonance scanner with cine, T2-weighted imaging with fat saturation and phase-sensitive inversion recovery. Global and segmental radial, circumferential and longitudinal strains were included for analysis. The extent of HighT2 was negatively correlated with global radial strain (ρ = -0.275, p = 0.038) and positively correlated with global circumferential strain (ρ = 0.308, p = 0.02) and global longitudinal strain (ρ = 0.422, p = 0.001). Radial, circumferential and longitudinal strains were all significantly associated with segment thickness. Regarding circumferential strain, segments at the mid-ventricular level with LGE and HighT2 showed more impairment than segments with only LGE. For longitudinal strain, the influence of HighT2 appeared only at the mid-ventricular level. The HighT2 extent in HCM was observed to contribute to global and segmental strain parameters. At the segmental level, HighT2 indeed affects left ventricular deformation, and follow-up studies are still warranted.

11.
J Mol Biol ; 431(6): 1113-1126, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30738893

RESUMO

SW1 is the first filamentous phage isolated from a deep-sea environment. Nevertheless, the mechanism by which the SW1 genetic switch is controlled is largely unknown. In this study, the function of the phage-encoded FpsR protein was characterized by molecular biological and biochemical analyses. The deletion of fpsR increased the copy number of SW1 ssDNA and mRNA, indicating that FpsR functions as a repressor. In addition, transcription from the fpsR promoter was shown to be increased in an fpsR deletion mutant, suggesting self-repression by FpsR. Purified FpsR bound to four adjacent operator sites (O1-O4) embedded within the fpsA promoter and the fpsA-fpsR intergenic region. A surface plasmon resonance experiment showed that FpsR can bind to the O1-O4 operators separately and with different binding affinity, and the dissociation constants of FpsR with O2 and O3 were found to be lower at 4 °C than at 20 °C. A gel permeation chromatography assay revealed that FpsR oligomerized to form tetramers. Point mutation analysis indicated that the C-terminal domain influenced the binding affinity and regulatory function of FpsR. Collectively, these data support a model in which FpsR actively regulates phage production by interacting with the corresponding operators, thus playing a crucial role in the SW1 genetic switch.

12.
J Magn Reson Imaging ; 50(4): 1075-1084, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30659687

RESUMO

BACKGROUND: Microstructural changes of lupus nephritis (LN) kidney such as inflammatory cell infiltration or fibrosis could influence water molecular movement or diffusion, which indicates that diffusion-weighted imaging (DWI) may become a valuable tool in evaluation of this disease. PURPOSE: To explore whether multiparameter diffusion-weighted imaging (mDWI) could contribute to characterize pathological patterns in LN patients. STUDY TYPE: Retrospective. POPULATION: Twenty-two patients with LN. FIELD STRENGTH/SEQUENCE: Multi-b value DWI was performed with a 3.0 T scanner. ASSESSMENT: Apparent diffusion coefficient (ADC)m , perfusion-related diffusion coefficient (Df ), molecular diffusion coefficient (Ds ), perfusion fraction (f), ADCs , α, ADCk , and mean kurtosis (MK) were calculated by monoexponential, biexponential, stretched-exponential, and kurtosis models fits, respectively. STATISTICAL TESTS: Independent sample t-test, Pearson analysis and receiver operating characteristic (ROC). RESULTS: In the whole group, the activity index (AI) correlated significantly with alpha values in the medulla (rho = -0.54, P = 0.03). The chronicity index (CI) correlated significantly with Ds values in the medulla (rho = -0.61, P = 0.02). No significant association was found between any other diffusion parameter and histologic grade with all P > 0.05. For differentiating proliferative LN (Class III or IV) from Class V, the area under the ROC curve (AUC) of alpha in the medulla was 0.833 (P = 0.023). DATA CONCLUSION: mDWI might be used for the characterization of pathological patterns in LN patients. LEVEL OF EVIDENCE: 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:1075-1084.

13.
Eur Radiol ; 29(8): 4447-4455, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30666451

RESUMO

OBJECTIVES: To assess the efficacy of diffusion kurtosis imaging (DKI) in differentiating low-grade from high-grade tumors and evaluating the aggressiveness of bladder cancer. METHODS: From January 2017 to July 2017, 35 patients (28 males, 7 females; mean age 63 ± 9 years) diagnosed with bladder cancer underwent diffusion-weighted imaging (DWI) with two types of DKI protocols: (1) multi-b value ranging from 0 to 2000 s/mm2 to obtain mean diffusivity/kurtosis (MDb/MKb) and (2) the tensor method with 32 directions with 3 b values (0, 1000, and 2000s/mm2) to obtain mean/axial/radial diffusivity (MDt/Da/Dr), mean/axial/radial kurtosis (MKt/Ka/Kr), and fractional anisotropy (FA) before radical cystectomy. Comparisons between the low- and high-grade groups, non-muscle-invasive bladder cancer (NMIBC), and muscle-invasive bladder cancer (MIBC) were performed with the areas under the receiver operating characteristic curves (AUCs). RESULTS: The MKt and Kr values were significantly (p = 0.017 and p = 0.048) higher in patients with high-grade bladder tumors than in those with low-grade tumors. The MKt, Kr, and MKb values were significantly (p = 0.022, p = 0.000, and p = 0.044, respectively) higher in patients with MIBC than in those with NMIBC, while no significant differences (p > 0.05) were found in other values. The AUC of Kr (0.883) was the largest and was significantly higher than those of other metrics (all p < 0.05) for differentiating MIBC from NMIBC, with a sensitivity and specificity of 81.8% and 91.7%, respectively. CONCLUSIONS: Kurtosis metrics performed better than diffusion metrics in differentiating MIBC from NMIBC, and directional kurtosis and Kr metrics may also have great potential in providing additional information regarding bladder cancer invasiveness. KEY POINTS: • Kurtosis metrics performed better than diffusion metrics in differentiating muscle-invasive bladder cancer (MIBC) from non-muscle-invasive bladder cancer (NMIBC). • Directional kurtosis can provide additional directional microstructural information regarding bladder cancer invasiveness.

14.
Org Biomol Chem ; 17(6): 1519-1530, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30681116

RESUMO

We report the identification of 14 novel anticancer agents through established computational anticancer cell-based models. Among these novel hits, the compound G03 exhibits stronger inhibitory effects on the proliferation of MCF-7, HepG2, MDA-MB-231, HCTT116, and HeLa as compared with the FDA-approved sorafenib, with IC50 values of 4.61, 3.20, 2.82, 2.98, and 2.90 µM, respectively. The tubulin protein was validated to be a target of G03 using SPR, tubulin polymerization, immunofluorescence, and western blot assays. G03 is a novel structurally simple anticancer agent with unusual microtubule-stabilizing effects. Our study demonstrated the identification of bioactive small molecules by computational phenotypic modeling, which represents a feasible route toward innovative leads for chemical biology and medicinal chemistry.


Assuntos
Antineoplásicos/farmacologia , Bioensaio , Microtúbulos/efeitos dos fármacos , Microtúbulos/metabolismo , Simulação de Acoplamento Molecular , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Conformação Proteica , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismo , Interface Usuário-Computador
15.
Sci Rep ; 8(1): 17619, 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30514959

RESUMO

Gastric cancer is one of the main diseases leading to cancer-related death. The recently introduced dual-energy spectral CT (DEsCT), allows to obtain many quantitative measurements from iodine-based material decomposition (MD) images, which contribute to improve the accuracy of staging of GC comparing to multidetector spiral CT. And Ki-67 is a well-recognized nuclear antigen-specific biomarker reflecting cellular proliferation for estimating growth fractions of various tumor types. In the present study we analyzed the features of quantitative measurements (the curve slope (λHU), IC, normalized iodine concentrations (NIC)) obtained from DEsCT and levels of Ki-67 protein expression. We demonstrated that the values between advanced gastric cancer (AGC) and early gastric cancer (EGC) were significantly different both in venous phase (VP) and delayed phase (DP). The values of different level of Ki-67 expression grade were significantly different both in VP and DP. The rank correlation analysis between Ki-67 grade and IC, NIC and λHU values showed significantly positive correlation in VP and DP. These results suggested that quantitative parameters (IC, NIC and λHU) in dual-energy CT imaging can be used to differentiate EGC from AGC, and have significantly positive correlation with Ki-67 antigen expression levels in gastric cancer for indicating tumor cellular proliferation.

16.
FASEB J ; : fj201800936R, 2018 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-30407877

RESUMO

SUMOylation is a significant post-translational modification (PTM) by the small ubiquitin-related modifier (SUMO). Increasing evidence shows SUMOylation regulates GPCR signaling; however, very few GPCRs have been shown to be SUMOylation targets to date. In this study, we identified M1 muscarinic acetylcholine receptor (M1 mAChR), a member of the GPCRs, as a new SUMO substrate. When the mAChR was activated by the agonist carbachol, the colocalization of the M1 mAChR and SUMO-1 protein markedly decreased in immunoprecipitation and immunofluorescence assays. SUMOylation of the M1 mAChR played an important role in increasing the ligand-binding affinity to M1 mAChR, signaling efficiencies, and receptor endocytosis. Through the site-directed mutagenesis approach, K327 was identified as the SUMOylation site of the M1 mAChR. Mutation of the consensus SUMOylation site of the M1 mAChR reduces not only the colocalization of SUMO-1, but also the ligand-binding affinity and signal transduction. The function of M1 mAChR was regulated by SUMOylation through the stabilization of active-state conformation revealed by molecular dynamics simulations. Our results provide evidence that M1 SUMOylation is an important PTM involved in regulation of the affinity for agonists and for activation of signaling pathways.-Xu, J., Tan, P., Li, H., Cui, Y., Qiu, Y., Wang, H., Zhang, X., Li, J., Zhu, L., Zhou, W., Chen, H. Direct SUMOylation of M1 muscarinic acetylcholine receptor increases its ligand-binding affinity and signal transduction.

17.
Nat Chem Biol ; 14(12): 1118-1126, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30374165

RESUMO

SIRT6, a member of the SIRT deacetylase family, is responsible for deacetylation of histone H3 Nε-acetyl-lysines 9 (H3K9ac) and 56 (H3K56ac). As a tumor suppressor, SIRT6 has frequently been found to have low expression in various cancers. Here, we report the identification of MDL-800, a selective SIRT6 activator. MDL-800 increased the deacetylase activity of SIRT6 by up to 22-fold via binding to an allosteric site; this interaction led to a global decrease in H3K9ac and H3K56ac levels in human hepatocellular carcinoma (HCC) cells. Consequently, MDL-800 inhibited the proliferation of HCC cells via SIRT6-driven cell-cycle arrest and was effective in a tumor xenograft model. Together, these data demonstrate that pharmacological activation of SIRT6 is a potential therapeutic approach for the treatment of HCC. MDL-800 is a first-in-class small-molecule cellular SIRT6 activator that can be used to physiologically and pathologically investigate the roles of SIRT6 deacetylation.

18.
Transl Neurodegener ; 7: 21, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30237878

RESUMO

Background: Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative brain disorder, which is the most common form of dementia. Intensive efforts have been made to find effective and safe treatment against AD. Acetylcholinesterase inhibitors (AChEIs) have been widely used for the treatment of mild to moderate AD. In this study, we investigated the effect of Bis(9)-(-)-Meptazinol (B9M), a novel potential dual-binding acetylcholinesterase (AChE) inhibitor, on learning and memory abilities, as well as the underlying mechanism in the APP/PS1 mouse model of AD. Methods: B9M (0.1 µg/kg, 0.3 µg/kg, and 1 µg/kg) was administered by subcutaneous injection into eight-month-old APP/PS1 transgenic mice for four weeks. Morris water maze, nest-building and novel object recognition were used to examine learning and memory ability. Aß levels and Aß plaque were evaluated by ELISA and immunochemistry. Results: Our results showed that chronic treatment with B9M significantly improved the cognitive function of APP/PS1 transgenic mice in the Morris water maze test, nest-building test and novel object recognition test. Moreover, B9M improved cognitive deficits in APP/PS1 mice by a mechanism that may be associated with its inhibition of the AChE activity, Aß plaque burden, levels of Aß and the consequent activation of astrocytes and microglia in the brain of APP/PS1 transgenic mice. Most of important, the most effective dose of B9M in the present study is 1 µg/kg, which is one thousand of the dosage of Donepezil acted as the control treatment. Furthermore, B9M reduced Aß plaque burden better than Donepezil. Conclusion: These results indicate that B9M appears to have potential as an effective AChE inhibitor for the treatment of AD with symptom-relieving and disease-modifying properties.

19.
Brain Imaging Behav ; 2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30178423

RESUMO

Although evidence has shown that the prevalence rates of Internet gaming disorder (IGD) differ between males and females, few studies have examined whether such sex differences extend to brain function. This study aimed to explore the sex differences in resting-state cerebral activity alterations in IGD. Thirty male participants with IGD (IGDm), 23 female participants with IGD (IGDf), and 30 male and 22 female age-matched healthy controls (HC) underwent resting-state functional MRI. Maps of the amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) were constructed. A two-factor ANCOVA model was performed, with sex and diagnosis as the between-subject factors. Then, post hoc pair-wise comparisons were performed using two-sample t-tests within the interaction masks. The Barratt Impulsiveness Scale-11 (BIS-11) was used to assess the behavioral inhibition function. We found that the ALFF values in the orbital part of the left superior frontal gyrus (SFG) were lower in IGDm than in HCm, which were negatively correlated with BIS-11 scores. IGDm also demonstrated lower connectivity between the orbital part of the left SFG and the posterior cingulate cortex (PCC), the right angular gyrus, and the right dorsolateral prefrontal cortex than HCm. Furthermore, IGDm had lower seed connectivity between the orbital part of the left SFG and the PCC than ICDf. Our findings suggest that (1) the altered ALFF values in the orbital part of the left SFG represent a clinically relevant biomarker for the behavioral inhibition function of IGDm; (2) IGD may interact with sex-specific patterns of FC in male and female subjects.

20.
J Magn Reson Imaging ; 2018 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-30142234

RESUMO

BACKGROUND: The use of native T1 mapping for evaluation of hypertrophic cardiomyopathy (HCM) is being explored, and its combination with histogram analysis may benefit the accuracy of such assessments. PURPOSE: To investigate the relationship of segmental left ventricular wall thickness (LVWT), myocardial fibrosis, and strain parameters with segmental histogram parameters of native T1 mapping in HCM patients. STUDY TYPE: Retrospective. SUBJECTS: Ninety-three HCM patients without previous cardiovascular diseases were included. FIELD STRENGTH/SEQUENCE: 3.0T cardiac MR. Steady-state free precession cine imaging, modified Look-Locker inversion recovery, phase-sensitive inversion recovery. ASSESSMENT: Images were assessed by three experienced radiologists. STATISTICAL TESTS: Mann-Whitney U-tests, area under the curve (AUC), Spearman's rank correlation, intraclass correlation coefficient, and Bland-Altman test were used for statistical analysis. RESULTS: A higher LVWT value correlated with higher means, minimums, 10th /25th /50th /75th /90th percentiles, maximums, kurtosis, entropy, and lower SD and energy of T1 mapping (P < 0.05 for all), with the correlation being stronger for entropy and energy (Spearman's rho = 0.439 and -0.413, respectively) than other parameters. Late gadolinium enhancement positive (LGE+) segments exhibited higher mean, minimum, 10th /25th /50th /75th /90th percentiles, maximum, entropy, and lower energy of T1 times than late gadolinium enhancement negative (LGE-) segments (P < 0.001 for all). Impaired strain function parameters (peak thickening and thickening rate in radial, circumferential, and longitudinal directions) demonstrated a weak correlation with higher entropy (P < 0.001 for all) and lower energy (P < 0.001 for all). DATA CONCLUSION: Histogram parameters of native T1 mapping provide more information than mean T1 times alone. Among these parameters, entropy and energy may correlate better with LVWT, myocardial late gadolinium enhancement, and strain parameters than mean T1 times in HCM patients. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. MAGN. RESON. IMAGING 2018.

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