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1.
Aquat Toxicol ; 222: 105469, 2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32179334

RESUMO

Phthalates are commonly used in plastic products in daily life. The endocrine-disrupting effects of phthalates have been widely reported. Accumulating evidence from human cohorts and lab animals indicate exposure to phthalates might impair neurodevelopment. However, the direct causal relationship and mechanism between phthalates with neurodevelopment and neurotoxicity have not been firmly established. We found that phthalates (i.e. DBP, DINP, BBP) disrupted the expression of estrogen receptors (esr1, esr2a, esr2b), and impaired neurogenesis in the brain of zebrafish during embryonic development. Moreover, the abnormal expression of estrogen receptors, especially esr2a, was partly rescued in zebrafish which exposed to phthalates, with the estrogen receptor antagonist tamoxifen. Hence, impaired neurogenesis of zebrafish exposed to phthalates was partly reversed by tamoxifen treatment. Moreover, our results show that induced pluripotent stem cells (iPSC)-derived human neurons exposed to phthalates triggered double-strand DNA breaks in vitro. Overall, this study demonstrates that exposure to phthalates affects neurodevelopment in zebrafish embryos and induces neurotoxicity in human neurons partly through disrupting the expression of estrogen receptors.

2.
BMC Urol ; 20(1): 29, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32188426

RESUMO

BACKGROUND: The robot-assisted radical prostatectomy (RARP) has been widely applied in recent years; however, only a few studies are reported about long-term urinary continence after surgery. The present study aimed to examine the outcomes of continence rates (CRs) and determine the risk and protective factors of urinary continence in patients with prostate cancer (PCa) undergoing RARP. METHODS: This retrospective study included 650 patients treated with RARP with perioperative data and at least one year of follow-up from September 2009 to November 2017. Also, the preoperative, intraoperative, and postoperative parameters of the patients were analyzed. Continence was defined as no pad use. Early and late continence was defined as the return of urinary continence within 3 months and beyond 12 months post-surgery, respectively. CRs were examined from 1 to 48 months postoperatively. Logistic regression analysis evaluated the association between the predictive factors and urinary continence in the early and late stages. RESULTS: No significant difference was detected in the CR from 12 to 48 months postoperatively (P = 0.766). Logistic regression analysis proved that pelvic lymph node dissection (PLND) was a significant risk factor of urinary continence at 1 month. Nerve-sparing (NS) was a significant protective factor of urinary continence at 1, 3, and 6 months. Advanced age was an independent risk factor of urinary continence at 6, 12, and 24 months. Other variables were not statistically significant predictors of urinary continence. CONCLUSIONS: The current results demonstrated that CR gradually improved with time within 1 year and stabilized 1 year after the surgery. PLND, NS, and age were significant determinants of continence in the early and late stages, respectively. These parameters could be used for preoperative identification of patients at high risk and counseling about postoperative expectations for urinary continence.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32195568

RESUMO

Hydrogen peroxide (H2O2) production by electrocatalytic two-electron oxygen reduction shows promise as a replacement for energy-intensive anthraquinonoid oxidation or H2/O2 direct synthesis. Here, we report on graphene-supported Ni single-atom electrocatalysts, which are synthesized by a simple surfactant-free reduction process with enhanced electrocatalytic activity and stability. Unlike conventional Ni nanoparticle or alloy catalysts, the well-dispersed Ni single-atom sites lack adjacent Ni atoms. This structure promotes H2O2 production by a two-electron oxygen reduction pathway under an alkaline condition (pH = 13). This catalyst exhibited enhanced H2O2 selectivity (94%) with a considerable mass activity (2.11 A mgNi-1 at 0.60 V vs. RHE), owing to the presence of oxygen functional groups and isolated Ni sites. Density functional theory calculations provide insights into the role of this catalyst in optimizing the two-electron oxygen reduction reaction pathway with high H2O2 selectivity. This work suggests a new method for controlling reaction pathways in atomically dispersed non-noble catalysts.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32152796

RESUMO

Endovascular therapy has been the first option for many vascular diseases. Due to the increasing development of endovascular devices and techniques in recent decades, endovascular procedures could be applied in treating those cases with complex anatomy. Two or three vascular access routes are required to establish through-and-through access in endovascular therapy for arterial occlusive disease and complex aortic aneurysm. Guidewire snaring with a snare kit is essential but sometimes time-consuming in the establishment of through-and-through access. To simplify the procedure, we design the magnetic kissing guidewire (MKG) with a magnetic tip that attracts each other to establish a guidewire route that meets the needs of clinical practice. We conducted the in vitro test to evaluate its magnetic force and the in vivo test to assess its performance in the arteries of twelve sheep. The results revealed that this novel guidewire significantly simplified the establishment of through-and-through access.

5.
Zhongguo Dang Dai Er Ke Za Zhi ; 22(3): 262-268, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32204764

RESUMO

OBJECTIVE: To study the differentially expressed mRNAs between MYCN-amplified neuroblastoma (NB) and non-amplified NB, to screen out the genes which can be used to predict the prognosis of MYCN-amplified NB, and to analyze their value in predicting prognosis. METHODS: NB transcriptome data and the clinical data of children were obtained from the TARGET database. According to the presence or absence of MYCN amplification, the children were divided into two groups: MYCN amplification (n=33) and non-MYCN amplification (n=121). The expression of mRNAs was compared between the two groups to obtain differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analysis was performed to investigate the main functions of DEGs. The Cox proportional-hazards regression model analysis was used to investigate the genes influencing the prognosis of MYCN-amplified NB. The children were divided into a high-risk group (n=77) and a low-risk group (n=77) based on the median of risk score. A survival analysis was used to compare survival rate between the two groups. The receiver operating characteristic (ROC) curve was used to investigate the value of risk score in predicting the prognosis of children with MYCN-amplified NB. RESULTS: A total of 582 DEGs were screened out, and they were involved in important biological functions such as ribosome composition, expression of cell adhesion molecules, and activity of membrane receptor protein. The multivariate Cox regression model analysis showed that FLVCR2, SCN7A, PRSS12, NTRK1, and XAGE1A genes had a marked influence on the prognosis of the children with NB in the MYCN amplification group (P<0.05). The survival analysis showed that the high-risk group had a significantly lower overall survival rate than the low-risk group (P<0.05). The ROC curve analysis showed that risk score had a certain value in predicting the prognosis of the children with NB in the MYCN amplification group (P<0.05), with an area under the ROC curve of 0.729, an optimal cut-off value of 1.316, a sensitivity of 53.2%, and a specificity of 84.4%. CONCLUSIONS: The mRNA expression of FLVCR2, SCN7A, PRSS12, NTRK1, and XAGE1A genes can be used as biomarkers to predict the prognosis of MYCN-amplified NB, which can help to refine clinical risk stratification.


Assuntos
Neuroblastoma , Criança , Amplificação de Genes , Humanos , Proteínas de Membrana Transportadoras , Proteína Proto-Oncogênica N-Myc , Prognóstico , RNA Mensageiro , Receptores Virais
6.
Int J Mol Sci ; 21(7)2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32218345

RESUMO

The study of protein-protein interaction is of great biological significance, and the prediction of protein-protein interaction sites can promote the understanding of cell biological activity and will be helpful for drug development. However, uneven distribution between interaction and non-interaction sites is common because only a small number of protein interactions have been confirmed by experimental techniques, which greatly affects the predictive capability of computational methods. In this work, two imbalanced data processing strategies based on XGBoost algorithm were proposed to re-balance the original dataset from inherent relationship between positive and negative samples for the prediction of protein-protein interaction sites. Herein, a feature extraction method was applied to represent the protein interaction sites based on evolutionary conservatism of proteins, and the influence of overlapping regions of positive and negative samples was considered in prediction performance. Our method showed good prediction performance, such as prediction accuracy of 0.807 and MCC of 0.614, on an original dataset with 10,455 surface residues but only 2297 interface residues. Experimental results demonstrated the effectiveness of our XGBoost-based method.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32130576

RESUMO

To evaluate the impact of an iterative reconstruction (IR) algorithm (advanced modeled iterative reconstruction, ADMIRE) on machine learning-based coronary computed tomography angiography-derived fractional flow reserve (CT-FFRML) measurements compared with filtered back projection (FBP). 170 plaque-containing vessels in 107 patients were included. CT-FFRML values were measured and compared among 5 imaging reconstruction algorithms (FBP and ADMIRE at strength levels of 1, 2, 3 and 5). The plaques were classified as, 'calcified" or "noncalcified" and "≥ 50% stenosis" or "< 50% stenosis', a total of four subgroups by consensus. There were no significant differences of CT-FFRML values among the FBP and ADMIRE 1, 2, 3 and 5 groups wherever comparisons were done at the level of subgroups (P = 0.676, 0.414, 0.849, 0.873, respectively) or overall (P = 0.072). There were 20, 21, 19, 19 and 29 vessels with lesion-specific ischemia (CT-FFRML ≤ 0.80) in FBP and ADMIRE 1, 2, 3 and 5 datasets, respectively, but no statistical differences were found (P = 0.437). Compared with CT-FFRML value of FBP dataset, the CT-FFRML values of 9 (5.3%) vessels from 8 patients (7.5%) in ADMIRE5 dataset switched from above 0.8 to below or equal to 0.8. There were no significant differences of the CT-FFRML values among the FBP and IR image algorithms at different strength levels. However, high iterative strength level (ADMIRE 5) was not recommended, which might have an impact on diagnosis of lesion-specific ischemia, although changes only occurred in a modest number of subjects.

8.
Biomed Res Int ; 2020: 7056056, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149125

RESUMO

Purpose: The aim of the present study was to evaluate the relationship of fluid-attenuated inversion recovery (FLAIR) vascular hyperintensities (FVH) with haemodynamic abnormality and severity of arterial stenosis in patients with transient ischemic attack (TIA) of the carotid artery system. Patients and Methods. Consecutive inpatients (N = 38) diagnosed with TIAs of the carotid system in a 4-year period (2014-2017) were retrospectively analysed in our study and divided into FVH-negative and FVH-positive groups based on the presence of FVH sign. Each inpatient had undergone magnetic resonance imaging (MRI) followed by computed tomography (CT) perfusion imaging studies. We investigated the degree of arterial stenosis, number of stenosis, watershed regions, and related CT perfusion indexes, including hypoperfusion regions, mean transit time (MTT), cerebral blood flow (CBF), and cerebral blood volume (CBV). Spearman rank correlation was performed between FVHs score, the degree of arterial stenosis, and CT perfusion indexes with significant difference. Results: Thirty-one patients (81.6%) observed with FVH sign were assigned to the FVH-positive group. The hypoperfusion regions, MTT, and CBF values were significantly different between the FVH-negative group and FVH-positive groups. Spearman correlation analysis showed significant positive correlations between hypoperfusion regions, MTT, and FVHs scores (r = 0.755 and 0.674, respectively, p < 0.01); a moderate negative correlation was found between CBF and FVHs scores (r = 0.755 and 0.674, respectively, p < 0.01); a moderate negative correlation was found between CBF and FVHs scores (r = 0.755 and 0.674, respectively, p < 0.01); a moderate negative correlation was found between CBF and FVHs scores (. Conclusion: Hyperintense vessels on FLAIR were closely associated with hypoperfused regions, MTT, and CBF values, which indicated that the presence of FVHs could be an important and convenient imaging marker of haemodynamic impairment in patients with TIA.

9.
Artigo em Inglês | MEDLINE | ID: mdl-32170493

RESUMO

PURPOSE: To identify the genetic cause of patients with primary ciliary dyskinesia (PCD) and male infertility from two unrelated Han Chinese families. METHODS: We conducted whole-exome sequencing of three individuals with PCD and male infertility from two unrelated Chinese families, and performed a targeted look-up for DNAAF6 variants in our previously reported cohort of 442 individuals (219 with isolated oligoasthenospermia and 223 fertile controls). Ultrastructural and immunostaining analyses of patients' spermatozoa were performed. The pathogenicity of the variants was validated using patient's spermatozoa and HEK293T cells. Intracytoplasmic sperm injection (ICSI) treatment was conducted in two patients. RESULTS: We identified one novel hemizygous frameshift variant (NM_173494, c.319_329del: p.R107fs) of DNAAF6 gene (previously named PIH1D3) in family 1 and one novel hemizygous missense variant (c.290G>T: p.G97V) in family 2. No hemizygous deleterious variants in DNAAF6 were detected in the control cohort of 442 individuals. Ultrastructural and immunostaining analyses of patients' spermatozoa showed the absence of outer and inner dynein arms in sperm flagella. Both variants were proven to lead to DNAAF6 protein degradation in HEK293T cells. Both patients carrying DNAAF6 variants underwent one ICSI cycle and delivered one healthy child each. CONCLUSION: We identified novel DNAAF6 variants causing male infertility and PCD in Han Chinese patients. This finding extended the spectrum of variants in DNAAF6 and revealed new light on the impact of DNAAF6 variants in sperm flagella.

10.
PLoS Negl Trop Dis ; 14(3): e0008049, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32126080

RESUMO

Dengue fever, a mosquito-borne viral disease in humans, has been endemic in many Southeast Asian countries. Since its first outbreak in 1978 in Foshan, Guangdong province, China, dengue has been continually epidemic in recent years in Guangdong, which raised the concern whether dengue infection is endemic in Guangdong. In this study, we performed phylogenetic, recombinant, and nucleotide variation analyses of 114 complete genome sequences of dengue virus serotypes 1-4 (DENV1-4) collected from 2013 to 2017 in 18 of 21 cities of Guangdong. Phylogenetic analyses revealed that DENV sequences did not form a single cluster, indicating that dengue fever was not endemic in Guangdong, although DENV1-4 co-circulated in Guangdong. Twenty intra-serotype recombinant isolates involving DENV1-4 were detected, but no inter-serotype recombinant events were identified in this study. Additionally, the most recombinant events were detected simultaneously in the gene NS3 of DENV1-4. Nucleotide variation analyses showed that no significant intra-serotype differences were observed, whereas more significant inter-subtype differences were discovered in non-structural genes than in structural genes. Our investigation will facilitate the understanding of the current prevalent status of dengue fever in Guangdong and contribute to designing more effective preventive and control strategies for dengue infection.

11.
Environ Pollut ; 262: 114347, 2020 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-32179231

RESUMO

Microplastics have attracted much attention in recent years as they can interact with pollutants in water environment. However, nanoplastics (NPs) with or without the surface functionalization modification have not been thoroughly explored. Here, the sorption behaviors of two fluoroquinolones (FQs), including norfloxacin (NOR) and levofloxacin (LEV) on polystyrene NPs (nano-PS) and carboxyl-functionalized polystyrene NPs (nano-PS-COOH) were investigated. The results showed that sorption isotherms were nonlinear and well fitted by Langmuir model. The sorption capacities of NOR and LEV on nano-PS-COOH were higher than those on nano-PS, and their physical interactions, including polar interaction, electrostatic interaction and hydrogen bonding may be the dominant mechanisms. Moreover, the increase of pH firstly increased the sorption of two FQs on NPs and then decreased because NOR and LEV had a reverse charge at different pH values. Salinity and dissolved organic matter both inhibited the sorption process. These findings show that NPs with or without the surface functionalization modification have different sorption behaviors for environmental pollutants, which deserve our further concern.

12.
J Hazard Mater ; 393: 122379, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32120217

RESUMO

A method combining g-C3N4 and potassium peroxydisulfate (PDS) under simulated sunlight was put forward to effectively degrade sulfamethoxazole (SMX). The SMX removal efficiency was substantially improved compared with the processes involving only g-C3N4 or PDS. The kinetic constants for the g-C3N4, PDS and g-C3N4/PDS systems were 0.0023, 0.0239 and 0.068 min-1, respectively. The g-C3N4/PDS process reached an SMX removal rate of 98.4 % after 60 min of simulated sunlight; in addition, the proposed system showed desirable efficiency for SMX degradation in two different actual water samples as well. The reaction mechanism was illustrated by trapping experiments, which showed that g-C3N4 can promote S2O82- to transfer SO4-, S2O82- favored the generation of O2-, and O2-, SO4- and holes (h+) were the main oxidative species for the SMX degradation in the combined reaction process under simulated sunlight. Then, to further explore this mechanism, the intermediates generated during the combined reaction process were analyzed by LC/MS and possible degradation pathways were proposed. The result showed that the breaking of the SN and C-S bonds, the hydroxylation of the benzene ring and the oxidation of the amino group were identified as the main pathways in the SMX degradation process by the g-C3N4/PDS system under simulated sunlight.

13.
Biomed Res Int ; 2020: 1340153, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32090065

RESUMO

Papillary thyroid carcinoma (PTC) is the most common subtype of differentiated thyroid cancers in Asian coastal cities, where the patients have increased risk of potentially high or excessive iodine intake. Given the high metastasis and recurrence of patients with BRAFV600E mutation, the mortality rate of thyroid cancer has recently shown an upward trend. A variety of therapies, including surgery, radiotherapy, and chemotherapy, have been used to treat thyroid cancer, but these therapies still have limitations, including postoperative complications, drug resistance, poor efficacy, or serious side effects. Recent studies have shown the potential of active ingredients derived from herbal medicine in inhibiting PTC via various cell signaling pathways. Some plant-derived compounds, such as apigenin, genistein, and curcumin, are also known to prevent and treat PTC. This article summarizes the recent advances in the structure-functional impact of anti-PTC active ingredients and their effects on PTC cells and tumor microenvironments with an emphasis on their challenges from basic research to clinical practice.

14.
J Ethnopharmacol ; 253: 112641, 2020 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-32017949

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Moslae Herba, a common traditional Chinese herb with special flavor, has potential for treating respiratory and gastrointestinal diseases. AIM OF THIS STUDY: Lung endothelial barrier dysfunction (LEBD) accelerates the pathogenesis of influenza A virus (IAV)-induced secondary acute lung injury. New strategies against LEBD provide benefits in prevention and treatment of IAV. Previous studies showed that flavonoids (MHF), main bioactivity fraction derived from M. Herba, exerted anti-inflammatory and antiviral activities, but the underlying protection of MHF against IAV-induced acute lung injury remained obscure. The present study was to investigate the protection of MHF against IAV-induced LEBD in vivo and in vitro. MATERIALS AND METHODS: Mice were intranasally challenged with IAV and orally administered with MHF for 5 days. The pulmonary hyperpermeability of infected mice was evaluated by Evans Blue staining and in vivo imaging. Serum levels of inflammatory cytokines and mediators were detected by ELISA assay. The transepithelial electrical resistance (TER) of human pulmonary microvascular endothelial cells (HPMVECs) was measured by using TER meter. The expressions of key proteins in NOX4-mediated NF-κB/MLCK pathways were determined by western blotting. RESULTS: MHF treatment reduced lung index, W/D ratios, and serum levels of inflammatory factors (IL-6, TNF-α, IL-1ß, PLA2, LBT4 and ICAM-1) in IAV-infected mice. Evans blue staining and in vivo imaging results revealed that MHF alleviated IAV-induced barrier dysfunction and pulmonary hyperpermeability. Moreover, luteolin and kaempferol, the main activity compounds in MHF, significantly inhibited TNF-α-induced HPMVEC apoptosis, and downregulated NF-κB/MLCK pathway by targeting NOX4. CONCLUSION: MHF attenuated IAV-induced barrier dysfunction by suppressing NOX4/NF-κB/MLCK pathway and may serve as a potential agent for the prevention of LEBD and IAV.

15.
Can J Microbiol ; : 1-8, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32040345

RESUMO

Iron is a fundamental element required by most organisms, including Brucella. Several researchers have suggested that the iron response regulator (irr) and rhizobial iron regulator (rirA) genes regulate iron acquisition by Brucella abortus, influencing heme synthesis by and virulence of this pathogen. However, little is known about another Brucella species, Brucella melitensis. In this research, we successfully constructed two mutants: M5-90Δirr and M5-90ΔrirA. The adhesion, invasion, and intracellular survivability of these two mutants were evaluated in RAW264.7 cells infected with 1 × 106 CFU of M5-90Δirr, M5-90ΔrirA, or M5-90. We also tested the sensitivity of cells to hydrogen peroxide and their ability to grow. In addition, the virulence of these two mutants was evaluated in BALB/c mice. The results showed that the ability of these two mutants to invade and adhere inside the murine macrophages RAW264.7 was attenuated but their ability to replicate intracellularly was strengthened, enhancing the resistance to hydrogen peroxide. The M5-90Δirr mutant showed stronger growth ability than the parental strain under iron-limiting conditions. No differences were observed in the number of bacteria in spleen between M5-90 and M5-90Δirr at 7 or 15 days postinfection. However, the number of M5-90ΔrirA in spleen reduced significantly at 15 days postinfection. The splenic index of the M5-90Δirr group is evidently lower than that of M5-90. This is the first report that irr and rirA genes of B. melitensis are associated not only with virulence but also with growth ability. Together, our data suggest that M5-90Δirr is a promising Brucella vaccine candidate.

16.
Artigo em Inglês | MEDLINE | ID: mdl-32091995

RESUMO

Multi-organ segmentation is a challenging task due to the label imbalance and structural differences between different organs. In this work, we propose an efficient cascaded V-Net model to improve the performance of multi-organ segmentation by establishing dense Block Level Skip Connections (BLSC) across cascaded V-Net. Our model can take full advantage of features from the first stage network and make the cascaded structure more efficient. We also combine stacked small and large kernels with an inception-like structure to help our model to learn more patterns, which produces superior results for multi-organ segmentation. In addition, some small organs are commonly occluded by large organs and have unclear boundaries with other surrounding tissues, which makes them hard to be segmented. We therefore first locate the small organs through a multi-class network and crop them randomly with the surrounding region, then segment them with a single-class network. We evaluated our model on SegTHOR 2019 challenge unseen testing set and Multi-Atlas Labeling Beyond the Cranial Vault challenge validation set. Our model has achieved an average dice score gain of 1.62 percents and 3.90 percents compared to traditional cascaded networks on these two datasets, respectively. For hard-to-segment small organs, such as the esophagus in SegTHOR 2019 challenge, our technique has achieved a gain of 5.63 percents on dice score, and four organs in Multi-Atlas Labeling Beyond the Cranial Vault challenge have achieved a gain of 5.27 percents on average dice score.

17.
Biomed Res Int ; 2020: 8954513, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32047817

RESUMO

PBX3 (Pre-B-cell leukemia homeobox 3) had been considered to be a multifunctional oncogene which involved in tumor growth, invasion, and metastasis in leukemia and some solid tumors. However, the contribution of PBX3 to papillary thyroid carcinoma (PTC) remains unclear. In this study, we found that PBX3 expression was significantly upregulated in PTC tissues compared to adjacent normal tissues, and high levels of PBX3 were correlated with tumor size, lymphatic metastasis, TMN stage, and poor prognosis of PTC patients. Overexpression of PBX3 in PTC cell lines promoted cell proliferation. Consistently, knockdown of PBX3 by shRNA induced cell cycle arrest at G0/G1 phase, and inhibited angiogenesis and tumor growth in vitro and in vivo. Furthermore, PBX3 promoted PTC cell proliferation and angiogenesis through activation of AT1R/VEGFR2 pathway while overexpression of AT1R and treatment with VEGFA reversed PBX3-shRNA-induced decreased phosphorylation of VEGFR2 and its downstream (ERK1/2, AKT and Src). It demonstrated that PBX3 could be used as a potential prognostic biomarker and therapeutic target for PTC.

18.
J Biomol Struct Dyn ; : 1-15, 2020 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-32036779

RESUMO

SHP2 is a non-receptor protein tyrosine phosphatase (PTP) encoded by the PTPN11 gene involved in cell death pathway (PD-1/PD-L1) and cell growth and differentiation pathway (MAPK). Moreover, mutations in SHP2 have been implicated in Leopard syndrome (LS), Noonan syndrome (NS), juvenile myelomonocytic leukemia (JMML) and several types of cancer and solid tumors. Thus, SHP2 inhibitors are much needed reagents for evaluation of SHP2 as a therapeutic target. A series of novel ethyl 4-(phenoxymethyl)-2-phenylthiazole-5-carboxylate derivatives were designed and synthesized, and their SHP2 inhibitory activities (IC50) were determined. Among the desired compounds, 1d shares the highest inhibitory activity (IC50 = 0.99 µM) against SHP2. Additionally, a common feature pharmacophore model was established to explain the structure activity relationship of the desired compounds. Finally, molecular dynamics simulation was carried out to explore the most likely binding mode of compound 1d with SHP2. In brief, the findings reported here may at least provide a new strategy or useful insights in discovering novel effective SHP2 inhibitors.Communicated by Ramaswamy H. Sarma.

19.
Aging (Albany NY) ; 12(3): 2507-2529, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-32023548

RESUMO

Osteosarcoma (OS) is the most common bone malignancy in adolescents and has poor clinical outcomes. Protein arginine methyltransferase 5 (PRMT5) has recently been shown to be aberrantly expressed in various cancers, yet its role in OS remains elusive. Here, we found that PRMT5 was overexpressed in OS and its overexpression predicted poor clinical outcomes. PRMT5 knockdown significantly triggered pronounced senescence in OS cells, as evidenced by the increase in senescence-associated ß-galactosidase (SA-ß-gal)-stained cells, induction of p21 expression, and upregulation of senescence-associated secretory phenotype (SASP) gene expression. In addition, we found that PRMT5 plays a key role in regulating DNA damaging agents-induced OS cell senescence, possibly, via affecting the repair of DNA damage. Furthermore, we found that TXNIP acts as a key factor mediating PRMT5 depletion-induced DNA damage and cellular senescence. Mechanistically, TRIM21, which interacts with PRMT5, was essential for the regulation of TXNIP/p21 expression. In summary, we propose a model in which PRMT5, by interaction with TRIM21, plays a key role in regulating the TXNIP/p21 axis during senescence in OS cells. The present findings suggest that PRMT5 overexpression in OS cells might confer resistance to chemotherapy and that targeting the PRMT5/TRIM21/TXNIP signaling may enhance the therapeutic efficacy in OS.

20.
Bioresour Technol ; 304: 123007, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32070841

RESUMO

Studying biohydrogen production from alfalfa is of practical significance to cleaner production and biomass utilization. The performances of biohydrogen production through active/passive saccharification and photo-fermentation were compared. The effects of initial pH, substrate concentration, and cellulase loading on biohydrogen production from alfalfa by photosynthetic bacteria HAU-M1 were presented. It was found that the maximum hydrogen yield of 55.81 mL/g was achieved at initial pH of 6.90, substrate concentration of 31.23 g/mL, and cellulase loading of 0.13 g/g. Hydrogen yield of active saccharification and photo-fermentation was much higher as compare to passive saccharification and photo-fermentation. Initial pH value showed a more significant influence on photosynthetic bacteria in comparison to cellulase in active saccharification and photo-fermentation biohydrogen production. The low yield of propionic acid suggested that it was an efficient photosynthetic hydrogen production. Photo-fermentation hydrogen production from alfalfa provides a novel path for efficient utilization of alfalfa.


Assuntos
Celulase , Medicago sativa , Biomassa , Fermentação , Hidrogênio
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