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1.
Diabetes Metab ; 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32035968

RESUMO

AIM: We aimed to evaluate the association between serum thyroid stimulating hormone (TSH) levels, within the reference range, and the histological severity of non-alcoholic fatty liver disease (NAFLD), and whether this association was modulated by the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 polymorphism. MATERIALS AND METHODS: We enrolled 327 euthyroid individuals with biopsy-proven NAFLD, who were subdivided into two groups, i.e., a 'strict-normal' TSH group (TSH level 0.4 to 2.5 mIU/l; n=283) and a 'high-normal' TSH group (TSH level 2.5 to 5.3 mIU/l with normal thyroid hormones; n=44). Logistic regression analyses were performed to assess the association between TSH status and presence of non-alcoholic steatohepatitis (NASH) after stratifying subjects by PNPLA3 genotypes. RESULTS: Compared to strict-normal TSH group, patients with high-normal TSH levels were younger and had a greater prevalence of NASH and higher histologic NAFLD activity score. After stratifying by PNPLA3 genotypes, the significant association between high-normal TSH levels and presence of NASH was restricted only to carriers of the PNPLA3 G risk allele and remained significant even after adjustment for potential confounding factors (adjusted-odds ratio 3.279; 95%CI 1.298-8.284; P = 0.012). CONCLUSION: In euthyroid individuals with biopsy-proven NAFLD, we found a significant association between high-normal TSH levels and NASH. After stratifying by PNPLA3 rs738409 genotypes, this association was observed only among carriers of the PNPLA3 G risk allele.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31973978

RESUMO

In order to develop an affinity HPLC method for screening direct thrombin inhibitors from Traditional Chinese Medicine (TCM), thrombin was immobilized on the glutaraldehyde-modified amino silica gel and was used as thrombin stationary phase. A thrombin affinity column (TAC) was made by packing the thrombin stationary phase into a bare column (2.0 * 1.0 mm, i.d.). The direct thrombin inhibitors could be screened through this TAC column. For the purpose of improvement of the discovery efficiency, a TAC-HPLC-MS/MS system was used to screen thrombin inhibitors from Radix Salviae Miltiorrhiae (RSM), a famous traditional Chinese medicine. After optimization of all the conditions, cryptotanshinone (Cry), dihydrotanshinone I (Dih-I) and tanshinone IIA (Tan-IIA) were screened out and identified as potential active components. The anticoagulant effects of these three compounds were tested by anticoagulant experiments in vitro. Furthermore, the interaction of three compounds with thrombin was studied by molecular docking. The result shows they have the potential to be used as preventive drugs. In short, this method can be used to screen anticoagulant drugs from traditional Chinese medicine, which provides convenience for screening anticoagulant drugs.

3.
Ophthalmic Res ; : 1-12, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31955159

RESUMO

IMPORTANCE: Retinopathy of prematurity (ROP) is an important risk factor for blindness in children due to neovascularization (NV). Hypoxia stimulates the formation of NV, as retinal hypoxia affects the stability and function of hypoxia-inducible factor (HIF) transcription factors. The purpose of this study is to study the mechanism of ROP and provide theoretical basis for clinical treatment of ROP. OBJECTIVE: In the present study, we used a mouse model of oxygen-induced retinopathy (OIR) to demonstrate the effects of the HIF-1α inhibitor PX-478 on OIR, and to determine its mechanism of action, to provide a theoretical basis for the clinical treatment of ROP. MATERIALS AND METHODS: The OIR mouse model was induced by exposing neonatal mouse pups and their mothers to 75 ± 5% oxygen from postnatal day 7 (P7) to P12, before being returned to room air from P12 to P17. Flat mount analyses were performed at P12 and P17. Hif1a, Hif2a, Hif3a, and Vegfa mRNA were detected by reverse transcription-polymerase chain reaction in OIR mice at P12 and P17. Hif1a and Vegfa mRNA were detected in OIR mice at P12 and P17 treatment with PX-478. Western blot analyses were used to assess the levels of HIF-1α, VEGF-A, and EPO before and after treatment with PX-478 at P12 and P17. RESULTS: Hif1a mRNA was increased in OIR mice at P12 and P17, while Vegfa mRNA was increased at P12 and P17. HIF-1α, VEGF-A, and EPO protein levels were increased in OIR mice at P12 and P17, as compared to control mice at the same age (all p < 0.05). Inhibition of HIF-1α by injection of PX-478 in OIR mice (P9-P16) caused a decrease in the retinal avascular area at P12 and P17 (both p < 0.05), NV areas at P17 (p < 0.05), Vegfa mRNA decreased at P12 and P17, as compared to control mice (p < 0.05), and VEGF-A and EPO protein levels at P12 and P17, as compared to control mice. Our study found that there were PX-478 both retina and vitreous body of OIR. Inhibition of HIF-1α by injection of PX-478 in OIR mice caused a decrease in the retinal avascular area at P12 and P17, NV areas decreased at P17, VEGF-A and EPO protein levels at P12 and P17. Endothelial cell migration assays and cell tube formation indication PX-478 attenuate cell migration and significantly weakened the cell cavity formation under the condition of hypoxia. CONCLUSION: HIF-1α plays a main role in OIR and can be considered a therapeutic target in OIR by suppressing downstream angiogenic factors, PX-478 decreasing the retinal avascular area and NV.

4.
Int J Biol Sci ; 16(1): 135-146, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31892851

RESUMO

Background: The 'adenoma-carcinoma sequence' is a well-recognized model of colorectal cancer (CRC) development. However, the interaction between gut microbiota and genetic variation in the initiation of CRC is not clear. Our study attempts to demonstrate the relationship between gut microbiota and host genetics in patients with intestinal adenomatous polyps. Method: The entire exon region of the APC gene was sequenced in 35 patients with pathologically diagnosed adenomatous polyps. Patients with highly pathogenic APC mutation were classified as the case group, while the others were classified as the control group. The patients'stool and serum samples were respectively collected for metagenomics and metabolomics measurements. Results: In the analysis of gut microbiome, there were three most important species, in which Fusobacterium_mortiferum was significantly increased while Faecalibacterium_prausnitzii and Bifidobacterium_pseudocatenulatum were significantly decreased in the case group. The significantly low abundance of the Photosynthesis pathway in patients with APC mutation was due to the low abundance of species Faecalibacterium_prausnitzii and Bifidobacterium_pseudocatenulatum. Moreover, there were two clusters of KEGG pathways correlated with two clusters of species characterized by Faecalibacterium_prausnitzii and Fusobacterium_mortiferum. As to serum metabolomics, the abundance of (R)-3-Hydroxybutyric acid and 2-Hydroxyphenethylamine were significantly higher in patients with APC mutation, while the abundance of 1-Aminocyclopropanecarboxylic acid,7-Ketocholesterol, DL-lactate, and L-Pyroglutamic acid were significantly higher in controlgroup. After analyzing the metabolome and microbiome data by sparCCmethod, we found that there was a significantly negative correlation between the abundance of Faecalibacterium_prausnitzii and Fusobacterium_mortiferum, and a significantly positive correlation between Faecalibacterium_prausnitzii abundance and the steroid hormone Hydrocortisone (Cortisol) in serum. Conclusions: Host's APC mutation was closely related to the changes of gut microbiota and serum metabolites, and some species of gut microbiome like Faecalibacterium_prausnitzii and Fusobacterium_mortiferum might have the potential to predict the development of CRC from intestinal adenomatous polyps.

5.
Drug Discov Today ; 25(1): 133-140, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31707121

RESUMO

Combining releasable chemical crosslinkers with photoaffinity probes represents a valuable tool for identifying protein-protein interactions (PPIs). The biomacromolecule photoaffinity probe prepared by using releasable photoaffinity linkers can be used to exploring PPIs by triggering release of the releasable group. More importantly, it can overcome the shortcomings of macromolecular photoaffinity probes without label transfer functionality to accurately confirm defects in specific structural sites. It shows particular promise for research exploring the interaction of unknown proteins and transient-weak PPIs in living organisms to discover new drug targets. In this review, we highlight recent progress in the development and application of chemical releasable linkers in photoaffinity probes. Several comparative studies are described in which the efficiency of various photoaffinity probes are compared.

6.
Liver Int ; 40(1): 107-119, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31519069

RESUMO

BACKGROUND & AIMS: Patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 polymorphism is associated with NAFLD severity and the PNPLA3 gene is expressed in the kidneys, but whether PNPLA3 rs738409 polymorphism is also associated with renal tubular injury (RTI) is uncertain. We assessed the effect of PNPLA3 genotypes on biomarkers of RTI and glomerular function in subjects with NAFLD who had either normal (nALT) or abnormal (abnALT) alanine aminotransaminase levels. METHODS: Two hundred and seventeen patients with histologically proven NAFLD of which 75 had persistently nALT (below upper limit of normal for 3 months) were included. Multivariable regression analyses were undertaken to test associations between PNPLA3 genotype and biomarkers of kidney dysfunction. RESULTS: The nALT patient group had higher urinary neutrophil gelatinase-associated lipocalin levels (u-NGAL, a biomarker of RTI) (P < .001), higher albuminuria (P = .039) and greater prevalence of chronic kidney disease (CKD; P = .046) than the abnALT group. The association between PNPLA3 GG genotype and risk of CKD and abnormal albuminuria remained significant after adjustment for kidney risk factors and severity of NAFLD histology, mostly in the nALT group. Similarly, PNPLA3 GG genotype was associated with higher u-NGAL levels in the nALT group, even after adjustment for the aforementioned risk factors and glomerular filtration-based markers (ß-coefficient: 22.29, 95% CI: 0.99-43.60, P = .041). CONCLUSION: Patients with NAFLD and persistently nALT, who carry the PNPLA3 rs738409 G allele, are at higher risk of early glomerular and tubular damage. We suggest PNPLA3 genotyping may help identify patients with NAFLD at higher risk of RTI.

7.
Eur J Gastroenterol Hepatol ; 32(1): 80-86, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31625959

RESUMO

OBJECTIVE: Insulin resistance (IR) has been established as a major risk factor for nonalcoholic fatty liver disease (NAFLD) where it exerts effects on plasma glucose homeostasis, cellular anabolism, and organ glucose uptake. Owing to paucity of studies focused on peripheral IR in relation to pathological outcome, we aim to investigate homeostatic model assessment of insulin resistance (HOMA-IR) by histological characteristics of NAFLD. METHODS: Liver biopsy of 588 patients was screened. After excluding etiologies other than NAFLD and factors contributing to IR, serum HOMA-IR was compared with patients' histologic features. Univariate and multivariate analyses were conducted to assess their relationship. Area under the receiver operating characteristic (AUROC) was calculated to assess the discriminatory ability of homeostatic model assessment of IR for advanced lobular inflammation (LI). RESULTS: We observed higher serum level of alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, and low-density lipoprotein as HOMA-IR increased. HOMA-IR is significantly associated with severity of LI (odds ratio = 1.222, 95% confidence interval = 1.135-1.315, P < 0.001), similar association remained after adjusting for age, BMI, hemoglobin A1c, alanine aminotransferase, aspartate aminotransferase, low-density lipoprotein, high-density lipoprotein, and triglycerides (odds ratio = 1.205, 95% confidence interval = 1.102-1.317, P < 0.001). HOMA-IR is discriminant of LI with AUROC = 0.832 and cutoff = 2.995 (sensitivity = 0.938, specificity = 0.569). CONCLUSION: This study demonstrated a strong and independent association of HOMA-IR with the severity of liver inflammation by histological evaluation in NAFLD patients without diabetes or metabolic syndrome, and its possible role in diagnosis of LI could be translated into clinical assessment of NAFLD patients with uncertainty of nonalcoholic steatohepatitis progression.

8.
Antiviral Res ; 174: 104666, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31760108

RESUMO

Argentine haemorrhagic fever (AHF) is a rodent-borne disease with a lethality as high as ~30%, which is caused by the New World arenavirus, Junín virus (JUNV). It was once a major epidemic in South America and puts millions of people in Argentina at risk. Here, we aimed to develop horse antibodies or antibody fragments against JUNV. Before preparing the horse antibodies, a strategy to efficiently generate horse antisera was established based on comparisons among immunogens and immunization methods in both mice and horses. Antisera against JUNV were finally obtained by vaccinating horses with vesicular stomatitis virus pseudotypes bearing JUNV GP. The horse antibodies IgG and F(ab')2 were subsequently demonstrated to effectively neutralize vesicular stomatitis virus pseudotypes bearing JUNV GP and to show some cross-neutralization against pathogenic New World arenaviruses. Further research revealed that Asp123 on GP1 is an important site for the binding of antibodies targeting mainly JUNV GP1 for neutralization. Collectively, this study presents an efficient strategy to develop horse antisera against JUNV and provides GP1-specific horse antibodies as potential therapeutics for AHF.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31677195

RESUMO

BACKGROUND AND AIM: Patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M (rs738409) genotype influences clinical/biochemical characteristics in patients with nonalcoholic fatty liver disease (NAFLD), but whether PNPLA3-I148M (rs738409) genotype also influences the diagnostic performance of noninvasive diagnostic tests for NAFLD is uncertain. Our aim was to investigate the differences in diagnostic performance of noninvasive diagnostic tests for NAFLD according to PNPLA3-I148M (rs738409) genotype. METHODS: Fifty-eight healthy controls and 349 patients with biopsy-proven NAFLD were included. Areas under the receiver operating characteristic curve (AUROCs) were calculated to predict hepatic steatosis (fatty liver index and hepatic steatosis index), nonalcoholic steatohepatitis (cytokeratin-18 M30 and M65), and significant fibrosis (≥F2 fibrosis) (fibrosis-4 and BARD), stratifying by rs738409 genotypes (CC and CG + GG groups). RESULTS: Fatty liver index and hepatic steatosis index showed good diagnostic performance for diagnosing steatosis only in the CG + GG group with AUROCs ranging from 0.819 to 0.832. Cytokeratin-18 M30 (AUROC = 0.688) and M65 (AUROC = 0.678) had suboptimal performance for diagnosing nonalcoholic steatohepatitis in the CG + GG group, whereas both had good performance (AUROC = 0.814 and 0.813, respectively) in the CC group. BARD score showed good performance in the CG + GG group compared with the CC group (AUROC = 0.805 and 0.532, respectively). Fibrosis-4 had suboptimal performance in the CG + GG group and good performance in the CC group (AUROC = 0.662 and 0.801, respectively). CONCLUSIONS: Diagnostic performance of noninvasive tests for NAFLD varied markedly according to PNPLA3 genotypes. Clinicians should be aware that PNPLA3 genotype limits the clinical utility of noninvasive diagnostic tests for diagnosing NAFLD.

10.
J Med Chem ; 62(22): 10098-10107, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31657556

RESUMO

Stapled peptides recapitulate the binding affinity and specificity of α-helices in proteins, resist proteolytic degradation, and may provide a novel modality against challenging drug targets such as protein-protein interactions. However, most of the stapled peptides have limited cell permeability or are impermeable to the cell membrane. We show herein that stapled peptides can be rendered highly cell-permeable by conjugating a cyclic cell-penetrating peptide to their N-terminus, C-terminus, or stapling unit. Application of this strategy to two previously reported membrane-impermeable peptidyl inhibitors against the MDM2/p53 and ß-catenin/TCF interactions resulted in the generation of potent proof-of-concept antiproliferative agents against key therapeutic targets.

11.
United European Gastroenterol J ; 7(8): 1124-1134, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31662869

RESUMO

Background: Fibrosis is deemed to be a pivotal determinant of the long-term prognosis in non-alcoholic fatty liver disease (NAFLD). Objective: We aimed to develop a novel nomogram-based non-invasive model to accurately predict significant fibrosis in patients with NAFLD. Methods: We designed a prospective cohort study including 207 patients with biopsy-proven NAFLD. Detailed anthropometric and fibrosis-related laboratory parameters were collected. A nomogram was established based on variables that were independently associated with significant fibrosis identified by the logistic regression model. Then it was compared with aspartate aminotransferase-to-platelet ratio index (APRI), NAFLD fibrosis score (NFS), FIB-4 and BARD score. Diagnostic accuracy was assessed according to area under the receiver operator characteristic curve (AUROC), sensitivity, specificity, positive and negative predictive values, and decision curve analysis. Results: Variables included in the nomogram were: waist-to-height ratio, hyaluronic acid, procollagen-III-peptide, chitinase-3-like protein 1, and cytokeratine-18 neoepitope M65. The discrimination ability of the nomogram (AUROC = 0.829, 95%CI 0.755-0.904) was significantly superior to APRI (AUROC = 0.670, 95%CI 0.563-0.777), NFS (AUROC = 0.601, 95%CI 0.480-0.722), FIB-4 (AUROC = 0.624, 95%CI 0.511-0.736) and BARD (AUROC = 0.579, 95%CI 0.459-0.699) for significant fibrosis (all p < 0.05). The nomogram showed a larger net benefit to aid in decision-making as to whether biopsy is required. Conclusions: This novel nomogram was more accurate, and achieved higher net benefit than APRI, NFS, FIB-4 and BARD to detect significant fibrosis. It can be useful as a non-invasive method to screen ≥F2 fibrosis in the overall population with NAFLD.

12.
J Virol ; 93(23)2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31511384

RESUMO

Lassa virus (LASV) is the causative agent of a fatal hemorrhagic fever in humans. The glycoprotein (GP) of LASV mediates viral entry into host cells, and correct processing and modification of GP by host factors is a prerequisite for virus replication. Here, using an affinity purification-coupled mass spectrometry (AP-MS) strategy, 591 host proteins were identified as interactors of LASV GP. Gene ontology analysis was performed to functionally annotate these proteins, and the oligosaccharyltransferase (OST) complex was highly enriched. Functional studies conducted by using CRISPR-Cas9-mediated knockouts showed that STT3A and STT3B, the two catalytically active isoforms of the OST complex, are essential for the propagation of the recombinant arenavirus rLCMV/LASV glycoprotein precursor, mainly via affecting virus infectivity. Knockout of STT3B, but not STT3A, caused hypoglycosylation of LASV GP, indicating a preferential requirement of LASV for the STT3B-OST isoform. Furthermore, double knockout of magnesium transporter 1 (MAGT1) and tumor suppressor candidate 3 (TUSC3), two specific subunits of STT3B-OST, also caused hypoglycosylation of LASV GP and affected virus propagation. Site-directed mutagenesis analysis revealed that the oxidoreductase CXXC active-site motif of MAGT1 or TUSC3 is essential for the glycosylation of LASV GP. NGI-1, a small-molecule OST inhibitor, can effectively reduce virus infectivity without affecting cell viability. The STT3B-dependent N-glycosylation of GP is conserved among other arenaviruses, including both the Old World and New World groups. Our study provided a systematic view of LASV GP-host interactions and revealed the preferential requirement of STT3B for LASV GP N-glycosylation.IMPORTANCE Glycoproteins play vital roles in the arenavirus life cycle by facilitating virus entry and participating in the virus budding process. N-glycosylation of GPs is responsible for their proper functioning; however, little is known about the host factors on which the virus depends for this process. In this study, a comprehensive LASV GP interactome was characterized, and further study revealed that STT3B-dependent N-glycosylation was preferentially required by arenavirus GPs and critical for virus infectivity. The two specific thioredoxin subunits of STT3B-OST MAGT1 and TUSC3 were found to be essential for the N-glycosylation of viral GP. NGI-1, a small-molecule inhibitor of OST, also showed a robust inhibitory effect on arenavirus. Our study provides new insights into LASV GP-host interactions and extends the potential targets for the development of novel therapeutics against Lassa fever in the future.

13.
Eur J Med Chem ; 178: 232-242, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185413

RESUMO

As a continuation to our research, a series of novel Bcr-Abl inhibitors incorporated with 6-phenyl-1H-indazol-3-amine as hinge binding moiety (HBM) were developed based on confirmation analysis. Biological results indicated that these compounds exhibited an enhanced inhibition against Bcr-AblWT and Bcr-AblT315I in kinases assays, along with improved anti-proliferative activities in K562 cell assays. In particular, compound Y9 displayed comparable potency with that of imatinib. It potently inhibited Bcr-AblWT and Bcr-AblT315I kinases with IC50 of 0.043 µM and 0.17 µM, respectively. Furthermore, compound Y9 inhibited the proliferation of K562 and K562R cells with IC50 of 1.65 µM and 5.42 µM, respectively. Therefore, 6-phenyl-1H-indazol-3amine as HBM, combined with flexible linker, is a successful strategy contribute to research on T315I mutant resistance, and compound Y9 could be served as a starting point for further optimization.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Indazóis/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/metabolismo , Benzamidas/síntese química , Benzamidas/química , Benzamidas/metabolismo , Benzamidas/farmacologia , Sítios de Ligação , Proliferação de Células/efeitos dos fármacos , Desenho de Drogas , Proteínas de Fusão bcr-abl/química , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib/farmacologia , Indazóis/síntese química , Indazóis/química , Indazóis/metabolismo , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Simulação de Acoplamento Molecular , Mutação , Piperazinas/síntese química , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacologia , Maleabilidade , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo
14.
Eur J Med Chem ; 163: 1-9, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503935

RESUMO

VEGFR-2, Tie-2, and EphB4 are essential for both angiogenesis and tumorigenesis. Herein, we developed a series of pyridines incorporated with 1,2,3-triazole as multi-target inhibitors based on the crystal structure alignment of the kinase domain of angiogenic RTKs. Biological results indicated that these multi-target inhibitors displayed considerable potential as novel anti-angiogenic agents. Among them, compound BD7 exhibited the most potent inhibition against the three RTKs simultaneously, and good activity on inhibiting viability of human umbilical endothelial cells. Therefore, 1,2,3-triazole could serve as a promising DFG binding group for multi-target inhibitors of VEGFR-2, Tie-2 and EphB4 bearing pyridine as hinge binding group.


Assuntos
Inibidores da Angiogênese/síntese química , Piridinas/química , Receptor EphB4/antagonistas & inibidores , Receptor TIE-2/antagonistas & inibidores , Triazóis/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Inibidores da Angiogênese/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas Quinases
15.
Sensors (Basel) ; 18(11)2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30400248

RESUMO

When the nodes in the network are deployed in the target area with an appropriate density, the effective aggregation and transmission of the data gathered in the monitoring area remain to be solved. The existing Compressed Sensing (CS) based on data aggregation schemes are accomplished in a centralized manner and the Sink node achieves the task of data aggregation. However, these existing schemes may suffer from load imbalance and coverage void issues. In order to address these problems, we propose a Compressed Sensing based on Fault-tolerant Correcting Data Aggregation (CS-FCDA) scheme to accurately reconstruct the compressed data. Therefore, the network communication overhead can be greatly reduced while maintaining the quality of the reconstructed data. Meanwhile, we adopt the node clustering mechanism to optimize and balance the network load. It is shown via simulation results, compared with other data aggregation schemes, that the proposed scheme shows obvious improvement in terms of the Fault-tolerant correcting capability and the network energy efficiency of the data reconstruction.

16.
Biochem Pharmacol ; 156: 511-523, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30170098

RESUMO

The existence of latent reservoirs of Human Immunodeficiency Virus type-1 (HIV-1) is a major obstacle in eliminating the virus. Thus, an urgent need exists for effective latency reversing agents (LRAs) based on the "shock and kill" strategy. Proteasome inhibitors were recently studied as LRAs, but were considered too toxic for clinical use. Here, we demonstrated that PR-957, a selective immunoproteasome inhibitor, effectively reactivated latent HIV-1 provirus in vitro and ex vivo. Our data also suggests that PR-957 has relatively low cytotoxicity. Furthermore, it does not influence global T cell activation and decreases the expression levels of HIV-1 receptors/co-receptors. We demonstrated synergistic activation of latent HIV-1 with PR-957 and Prostratin (a protein kinase C activator) that alleviated the extent of T cell activation induced by Prostratin. In addition, PR-957 exhibited latency reversing efficacy through activating p-TEFb mediated by HSF-1 pathway. Moreover, PR-957 did not affect the activity of combination antiretroviral therapy (cART) drugs and the PR-957-reactivated virus was effectively inhibited with cART drugs. In conclusion, the immunoproteasome inhibitor PR-957 is a promising candidate LRA for future HIV-1 eradication strategies.


Assuntos
HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Fatores de Transcrição de Choque Térmico/metabolismo , Oligopeptídeos/farmacologia , Fator B de Elongação Transcricional Positiva/metabolismo , Latência Viral/efeitos dos fármacos , Linfócitos T CD4-Positivos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Fatores de Transcrição de Choque Térmico/genética , Humanos , Estrutura Molecular , Oligopeptídeos/química , Inibidores de Proteassoma/química , Inibidores de Proteassoma/farmacologia
17.
Horm Metab Res ; 50(9): 683-689, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30184562

RESUMO

Although several risk factors for metabolic syndrome (MetS) have been reported, there are few clinical scores that predict its incidence. Therefore, we created and validated a risk score for prediction of 3-year risk for MetS. Three-year follow-up data of 4395 initially MetS-free subjects, enrolled for an annual physical examination from Wenzhou Medical Center were analyzed. Subjects at enrollment were randomly divided into the training and the validation cohort. Univariate and multivariate logistic regression models were employed for model development. The selected variables were assigned an integer or half-integer risk score proportional to the estimated coefficient from the logistic model. Risk scores were tested in a validation cohort. The predictive performance of the model was tested by computing the area under the receiver operating characteristic curve (AUROC). Four independent predictors were chosen to construct the MetS risk score, including BMI (HR=1.906, 95% CI: 1.040-1.155), FPG (HR=1.507, 95% CI: 1.305-1.741), DBP (HR=1.061, 95% CI: 1.002-1.031), HDL-C (HR=0.539, 95% CI: 0.303-0.959). The model was created as -1.5 to 4 points, which demonstrated a considerable discrimination both in the training cohort (AUROC=0.674) and validation cohort (AUROC=0.690). Comparison of the observed with the estimated incidence of MetS revealed satisfactory precision. We developed and validated the MetS risk score with 4 risk factors to predict 3-year risk of MetS, useful for assessing the individual risk for MetS in medical practice.


Assuntos
Síndrome Metabólica , Modelos Biológicos , Adulto , Índice de Massa Corporal , Feminino , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/patologia , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Risco
18.
Mol Immunol ; 101: 471-478, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30114619

RESUMO

TIPE2 participates in multiple types of cancer development. However, its mechanism underlying chemoresistance in osteosarcoma has not been elucidated. Herein, we observed the expression of TIPE2 and MDR1 in cis-platin-resistant osteosarcoma tissues and cell lines. Compared to their matched sensitive cell lines and tissues, TIPE2 was downregulated while MDR1 expression was increased. Further investigation showed that overexpression of TIPE2 effectively inhibited MDR1 expression and greatly sensitized osteosarcoma cells to cis-platin, both in vivo and in vitro. Mechanistically, TIPE2 inhibited the transcription of the MDR1 promoter by interfering with the TAK1-NF-κB and -AP-1 pathways. Overall, our results elucidated for the first time that TIPE2 sensitizes osteosarcoma cells to cis-platin through downregulation of MDR1 and may be a novel target in osteosarcoma therapy.


Assuntos
Cisplatino/farmacologia , Regulação para Baixo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , NF-kappa B/metabolismo , Osteossarcoma/metabolismo , Fator de Transcrição AP-1/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Animais , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Osteossarcoma/patologia , Transdução de Sinais/efeitos dos fármacos , Transcrição Genética/efeitos dos fármacos
19.
Clin Chim Acta ; 485: 119-125, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29958887

RESUMO

AIMS: In order to investigate the effects and mechanism of Bisphenol A (BPA) on the growth of preantral follicles and the maturation of oocytes in vitro, preantral follicles were harvested from mouse ovaries and in vitro cultured for 11 days with different concentrations of BPA (0, 4.5 and 45 µM) for calculating the percentages of antral follicles, denuded oocytes, degenerative oocytes and the maturation rate of oocytes, besides measuring the diameter of follicles and the thickness of cumulus cell layers. METHODS: The contents of estradiol (E2) in the culture media on Day 4, 8 and 10 were detected by ELISA. The estrogen receptor (ER) expression, spindle morphology and chromosome distribution in oocytes on Day 10 and 11 were observed by immunofluorescence. Western blotting was used to detect the expressions of growth differentiation factor 9 (GDF-9), bone morphogenetic protein-15 (BMP-15), phosphorylated extracellular signal-regulated kinase 1 (p-Erk1) and phosphorylated Ca2+/calmodulin-dependent protein kinase II (p-CaMKII) in the oocytes. RESULTS: Compared with control, BPA (45 µM) significantly reduced percentages of antral follicles (9.25% vs. 91.17%, P < 0.05) and the maturation rate of oocytes (7.61% vs. 79.83%, P < 0.05), but increased the percentages of denuded oocytes (30.29% vs. 3.36%, P < 0.05) and degenerative oocytes (45.70% vs. 2.45%, P < 0.05). The diameter of follicles and the thickness of the cumulus cell layers were decreased significantly (P < 0.05). Moreover, BPA (45 µM) significantly decreased E2 contents in the culture medium on Day 8 and 10 (P < 0.05) and the expressions of ER, GDF-9 and BMP-15 in oocytes (P < 0.05). Furthermore, BPA (4.5 and 45 µM) treatment resulted in the abnormal spindle morphology and chromosome distribution, and the decreased expressions of p-Erk1 and p-CaMKII in the MII oocytes. CONCLUSION: Together, these results clearly demonstrated BPA retarded the preantral follicle growth in vitro through interfering with the synthesis and secretion of E2 and reducing the expressions of ER, GDF-9 and BMP-15, and led to the abnormal meioses of oocytes through reducing p-Erk1 and p-CaMKII expressions in the preantral follicles, which will help us to further unsderstand the mechanism of BPA exposure retarding in vitro growth of preantral follicles and maturation of oocyes.


Assuntos
Compostos Benzidrílicos/toxicidade , Células da Granulosa/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Oócitos/crescimento & desenvolvimento , Folículo Ovariano/efeitos dos fármacos , Folículo Ovariano/crescimento & desenvolvimento , Fenóis/toxicidade , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proliferação de Células/efeitos dos fármacos , Feminino , Células da Granulosa/metabolismo , Camundongos , Camundongos Endogâmicos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Oócitos/metabolismo , Folículo Ovariano/metabolismo
20.
Dig Dis ; 36(6): 427-436, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30048963

RESUMO

BACKGROUNDS AND AIMS: Previous studies have investigated that sarcopenia is associated with nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis, and fibrosis in NAFLD. The study aims to investigate the risk for NAFLD, especially NAFLD-related significant fibrosis among subjects with sarcopenia. METHODS: We searched electronic databases until 30, September 2017 and reviewed literature extensively. Effect estimates were pooled using random effect models regarding the risk for NAFLD and fixed effect models concerning the risk for significant fibrosis among sarcopenia patients. Sensitivity analysis was performed for the risk of NAFLD. RESULTS: We identified 6 studies. Our results showed that subjects with sarcopenia exhibited an increased risk for NAFLD compared to those without sarcopenia (OR 1.29, 95% CI 1.12-1.49) with heterogeneity among the individual studies (I2 = 61%). And the risk for NAFLD-related significant fibrosis appeared to be more pronounced in sarcopenia patients (OR 1.57, 95% CI 1.29-1.90) with an I2 of 0%. Sensitivity analysis revealed that neither the direction nor the magnitude of the estimated pooled results for NAFLD was obviously affected. Furthermore, the pooled ORs were both close to initial analysis when omitting the study by Hong et al. [Hepatology 2014; 59: 1772-1778] (OR 1.24, 95% CI 1.11-1.39, I2 = 47%) or by Hashimoto et al. [Endocr J 2016; 63: 877-884] (OR 1.33, 95% CI 1.11-1.59, I2 = 67%), which were considered sources of heterogeneity. CONCLUSIONS: Our analysis demonstrated that sarcopenia served not only as a risk factor for the onset of NAFLD but also related to the progression of NAFLD-related significant fibrosis.


Assuntos
Progressão da Doença , Cirrose Hepática/complicações , Hepatopatia Gordurosa não Alcoólica/complicações , Sarcopenia/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Viés de Publicação , Fatores de Risco
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