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1.
Cancer Biol Ther ; : 1-11, 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33064958

RESUMO

FGF13, a member of the FGF subfamily, has been found to be highly expressed in cancer cells such as prostate cancer, melanoma, glioma and multiple myeloma. However, the mechanism of FGF13 function during cancer cell proliferation remains to be unexplored, especially Non-small cell lung cancer (NSCLC). In this study, the cell proliferation effect of FGF13 on A549 cells was checked by CCK-8, clone formation, Ki67 immunofluorescence staining and Flow Cytometry assay. Localization of FGF13 within A549 cells was performed with confocal laser scanning microscope. The protein variations and interaction were measured by western blotting and co-immunoprecipitation analysis. It showed that FGF13 was mainly distributed in the cytoplasm and exhibited a high expression level in A549 cells. High expression of FGF13 activated AKT-GSK3 signaling pathway, and inhibited the activity of p21 and p27. Thus, FGF13 enhanced the process of transition from G1 to S phase and promoted A549 cells proliferation. Furthermore, the interaction between FGF13 and SHCBP1 was confirmed. Meanwhile, FGF13 and SHCBP1 had a cooperative effect to accelerate the cell cycle progression, especially the ability to promote cell proliferation is significantly enhanced via protein interaction. Hence, we conclude that FGF13 played a positive regulation role during A549 cells proliferation. FGF13 interacted with SHCBP1 to facilitate cell cycle progression, providing new insights into deep understanding of non-small cell lung cancer mechanisms of proliferation and regulation function of FGF13.

2.
Theranostics ; 10(24): 10925-10939, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042262

RESUMO

Rationale: Brain metastasis in patients with lung cancer is life-threatening. However, the molecular mechanism for this catastrophic disease remains elusive, and few druggable targets are available. Therefore, this study aimed to identify and characterize proteins that could be used as therapeutic targets. Methods: Proteomic analyses were conducted to identify differentially expressed membrane proteins between brain metastatic lung cancer cells and primary lung cancer cells. A neuronal growth-associated protein, brain acid soluble protein 1 (BASP1), was chosen for further investigation. The clinical relevance of BASP1 in lung adenocarcinoma was first assessed. Tyrosine kinase activity assays and in vitro and in vivo functional assays were conducted to explore the oncogenic mechanisms of BASP1. Results: The protein levels of BASP1 were positively associated with tumor progression and poor prognosis in patients with lung adenocarcinoma. Membrane-bound BASP1 increased EGFR signaling and stabilized EGFR proteins by facilitating their escape from the ubiquitin-proteasome pathway. Reciprocally, activation of EGFR recruited more BASP1 to the plasma membrane, generating a positive feedback loop between BASP1 and EGFR. Moreover, the synergistic therapeutic effects of EGFR tyrosine kinase inhibitor and arsenic trioxide led to a reduction in the level of BASP1 protein observed in lung cancer cells with acquired resistance to EGFR inhibitors. Conclusions: The reciprocal interaction between BASP1 and EGFR facilitates EGFR signaling in brain metastatic lung cancer. Targeting the newly identified BASP1-EGFR interaction could open new venues for lung cancer treatment.

3.
Int J Mol Sci ; 21(19)2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33023073

RESUMO

Protein phosphorylation can induce signal transduction to change sperm motility patterns during sperm capacitation. However, changes in the phosphorylation of sperm proteins in mice are still incompletely understood. Here, capacitation-related phosphorylation in mouse sperms were firstly investigated by label-free quantitative (LFQ) phosphoproteomics coupled with bioinformatics analysis using ingenuity pathway analysis (IPA) methods such as canonical pathway, upstream regulator, and network analysis. Among 1632 phosphopeptides identified at serine, threonine, and tyrosine residues, 1050 novel phosphosites, corresponding to 402 proteins, were reported. Gene heatmaps for IPA canonical pathways showed a novel role for GSK-3 in GP6 signaling pathways associated with capacitation for 60 min. At the same time, the reduction of the abundant isoform-specific GSK-3α expression was shown by western blot (WB) while the LFQ pY of this isoform slightly decreased and then increased. The combined results from WB and LFQ methods explain the less inhibitory phosphorylation of GSK-3α during capacitation and also support the predicted increases in its activity. In addition, pAKAP4 increased at the Y156 site but decreased at the Y811 site in a capacitated state, even though IPA network analysis and WB analysis for overall pAKAP revealed upregulated trends. The potential roles of GSK-3 and AKAP4 in fertility are discussed.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33051132

RESUMO

BACKGROUND: Chronic hepatitis B (CHB) patients who had exposed to lamivudine (LAM) and telbivudine (LdT) had high risk of developing entecavir (ETV)-resistance after long-term treatment. We aimed to conduct a systematic review and a network meta-analysis on the efficacy and cost-effectiveness on antiviral regimens in CHB patients with ETV-resistance. DATA SOURCES: We searched PubMed, EMBASE and Web of Science for studies on nucleos(t)ide analogues (NAs) treatment [including tenofovir disoproxil fumarate (TDF)-based rescue therapies, adefovir (ADV)-based rescue therapies and double-dose ETV therapy] in CHB patients with ETV-resistance. The network meta-analysis was conducted for 1-year complete virological response (CVR) and biological response (BR) rates using GeMTC and ADDIS. A cost-effective analysis was conducted to select an economic and effective treatment regimen based on the 1-year CVR rate. RESULTS: A total of 6 studies were finally included in this analysis. The antiviral efficacy was estimated. On network meta-analysis, the 1-year CVR rate in ETV-TDF [odds ratio (OR)  = 22.30; 95 % confidence interval (CI): 2.78 to 241.93], LAM-TDF (OR  = 70.67; 95 % CI: 5.16 to 1307.45) and TDF (OR  = 16.90; 95 % CI: 2.28 to 186.30) groups were significantly higher than that in the ETV double-dose group; the 1-year CVR rate in LAM-TDF (OR  = 14.82; 95 % CI: 1.03 to 220.31) was significantly higher than that in LAM/LdT-ADV. The 1-year BR rate of ETV-TDF (OR = 28.68; 95 % CI: 1.70 to 1505.08) and TDF (OR = 21.79; 95 % CI: 1.43 to 1070.09) therapies were significantly higher than that of ETV double-dose. TDF-based therapies had the highest possibility to achieve the CVR and BR at 1 year, in which LAM-TDF combined therapy was the most effective regimen. The ratio of cost/effectiveness for 1-year treatment was 8 526, 17 649, 20 651 Yuan in the TDF group, TDF-ETV group, and ETV-ADV group, respectively. CONCLUSIONS: TDF-based combined therapies such as ETV-TDF and LAM-TDF therapy were the first-line treatment if financial condition is allowed.

5.
Int J Chron Obstruct Pulmon Dis ; 15: 2257-2266, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33061343

RESUMO

Background: Fractional exhaled nitric oxide (FENO) has been shown to be a marker of airway inflammation in various pulmonary diseases, including chronic obstructive pulmonary disease (COPD). In this study, we assessed the FENO level in patients with acute exacerbations of COPD (AECOPD) and analyzed the predictive value of the FENO level for treatment response. Methods: Demographic data were collected at admission. FENO, lung function, blood gases, COPD Assessment Test (CAT), and modified Medical Research Council (mMRC) scores were measured at admission and on day 7. At the second visit, the patients were asked to report their health status; scores ranged from 1 to 5, representing "much better", "slightly better", "no change", "slightly worse", and "much worse", respectively. The treatment response was evaluated based on the patient's reported health status (responders were those who reported much better and slightly better) and lung function (responders were those who presented an increase in FEV1 over 200 mL). Results: A total of 182 patients were recruited into the analysis. The FENO level positively correlated with an increase in FEV1 and FEV1% (r = 0.291, p < 0.001 and r = 0.205, p = 0.005, respectively), but negatively correlated with a decrease in the COPD Assessment Test (CAT) score (r = -0.197, p = 0.008) and patient-reported health status (rho = -0.408, p<0.001). An inverse correlation was observed between FENO concentrations at admission and the length of hospital stay. The cut-off point for differentiating responders, identified by health status, was 18 ppb, with the sensitivity being 89.7% and specificity 88.9%. Conclusion: FENO levels, determined at hospital admission, are potential to predict the overall treatment response in AECOPD patients, including remission in subjective patient-reported health statuses and, also, improvements in lung function. Registry Number: ChiCTR-ROC-16,009,087 (http://www.chictr.org.cn/).

6.
Cell Rep ; 33(3): 108294, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33086053

RESUMO

The UbiA superfamily of intramembrane prenyltransferases catalyzes an isoprenyl transfer reaction in the biosynthesis of lipophilic compounds involved in cellular physiological processes. Digeranylgeranylglyceryl phosphate (DGGGP) synthase (DGGGPase) generates unique membrane core lipids for the formation of the ether bond between the glycerol moiety and the alkyl chains in archaea and has been confirmed to be a member of the UbiA superfamily. Here, the crystal structure is reported to exhibit nine transmembrane helices along with a large lateral opening covered by a cytosolic cap domain and a unique substrate-binding central cavity. Notably, the lipid-bound states of this enzyme demonstrate that the putative substrate-binding pocket is occupied by the lipidic molecules used for crystallization, indicating the binding mode of hydrophobic substrates. Collectively, these structural and functional studies provide not only an understanding of lipid biosynthesis by substrate-specific lipid-modifying enzymes but also insights into the mechanisms of lipid membrane remodeling and adaptation.

7.
Int J Mol Sci ; 21(20)2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33096780

RESUMO

ADAM9 (A disintegrin and a metalloprotease 9) is a membrane-anchored protein that participates in a variety of physiological functions, primarily through the disintegrin domain for adhesion and the metalloprotease domain for ectodomain shedding of a wide variety of cell surface proteins. ADAM9 influences the developmental process, inflammation, and degenerative diseases. Recently, increasing evidence has shown that ADAM9 plays an important role in tumor biology. Overexpression of ADAM9 has been found in several cancer types and is correlated with tumor aggressiveness and poor prognosis. In addition, through either proteolytic or non-proteolytic pathways, ADAM9 promotes tumor progression, therapeutic resistance, and metastasis of cancers. Therefore, comprehensively understanding the mechanism of ADAM9 is crucial for the development of therapeutic anti-cancer strategies. In this review, we summarize the current understanding of ADAM9 in biological function, pathophysiological diseases, and various cancers. Recent advances in therapeutic strategies using ADAM9-related pathways are presented as well.

8.
Sci Adv ; 6(43)2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33097544

RESUMO

"Magneto-optical" effect refers to a rotation of polarization plane, which has been widely studied in traditional ferromagnetic metal and insulator films and scarcely in two-dimensional layered materials. Here, we uncover a new nonreciprocal magnetophonon Raman scattering effect in ferromagnetic few-layer CrI3 We observed a rotation of the polarization plane of inelastically scattered light between -20o and +60o that are tunable by an out-of-plane magnetic field from -2.5 to 2.5 T. It is experimentally observed that the degree of polarization can be magnetically manipulated between -20 and 85%. This work raises a new magneto-optical phenomenon and could create opportunities of applying two-dimensional ferromagnetic materials in Raman lasing, topological photonics, and magneto-optical modulator for information transport and storage.

9.
Sci Rep ; 10(1): 17817, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33082357

RESUMO

Pancreatic cancer is the fourth leading cause of death worldwide due to its poorest prognoses with a 7% 5-year survival rate. Eighty percent of pancreatic cancer patients relapse after chemotherapy and develop early metastasis and drug resistance. Resistance to nucleoside analog gemcitabine frequently used in first-line therapy is an urgent issue in pancreatic cancer treatment. Expression of mucin (MUC) glycoproteins has been shown to enhance chemoresistance via increased cell stemness. Here we show interlukine-17 receptor B (IL-17RB) expression is positively correlated with MUC1 and MUC4 expression in pancreatic cancer cells and tumor tissue. Moreover, IL-17RB transcriptionally up-regulates expression of MUC1 and MUC4 to enhance cancer stem-like properties and resistance to gemcitabine. These results suggest IL-17RB can be a potential target for pancreatic cancer therapy. Indeed, treatment with IL-17RB-neutralizing antibody has a synergistic effect in combination with gemcitabine for killing pancreatic cancer cells. Altogether, these findings provide feasible applications for IL-17RB-targeting therapy in pancreatic cancer treatment.

10.
Dalton Trans ; 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33026381

RESUMO

Two new bifunctional isolated hybrid compounds, [ε-PMoV8MoVI4O37(OH)3Zn4][iql]4·6H2O (1) and [ε-PMoV8MoVI4O38(OH)2Zn4][bipy]3[(CH3COO)(bipy)2Zn]·2H2O (2) (where iql = isoquinoline and bipy = 2,2'-bipyridine), based on Zn-ε-Keggin were successfully synthesized by self-assembly under hydrothermal conditions. It is interesting to note that acetate in 2 acted as a linker connecting the ε-Keggin anion with the one Zn atom (Zn5) and enabled the ε-Keggin anion to coordinate with more bipy ligands, culminating with a larger isolated system, which is the first reported isolated cluster of Zn5PMo12. Meanwhile, compounds 1-2 show great electrochemical behaviors and excellent electrocatalytic activity for the degradation of NaNO2. In addition, compound 2 displays better third-order NLO performance than 1 due to the presence of more conjugated rings, with a TPA cross section (σ) of 1819 GM, which suggests that compound 2 has the potential to function as a bifunctional material with tremendous prospects.

11.
Mikrochim Acta ; 187(11): 607, 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33052497

RESUMO

A novel non-enzyme electrochemical biosensor for the rapid detection of Gram-positive bacteria has been constructed that relys on a stable and efficient combination between the peptidoglycan layer and platinum-nickel-copper nanocubes (Pt-Ni-Cu NCs). Briefly, bacteria were first captured by a specific antibody. Then, the electrochemical signal materials (Pt-Ni-Cu NCs) were bound to the bacteria peptidoglycan layer using specific structural and surface features. The rapid and sensitive bacterial detection was then achieved using intrinsic electrochemical characteristics and superoxidase-like activity of the Pt-Ni-Cu NCs. Moreover, the nature of peptidoglycan covering the whole bacteria provided the premise for signal amplification. Under optimal conditions, the electrochemical signal variation was proportional to the concentration of bacteria ranging from 1.5 × 102 to 1.5 × 108 CFU/mL with a detection limit of 42 CFU/mL using a working potential of - 0.4 V. This electrochemical biosensor has been successfully applied to detect bacteria concentrations in urine samples, and the recoveries range from 90.4 to 107%. The proposed biosensor could be applied for broad-spectrum detection of Gram-positive bacteria since most Gram-positive bacteria possess a thick peptidoglycan layer. The developed electrochemical biosensing strategy might be used as a potential tool for clinical pathogenic bacteria detection and point-of-care testing (POCT).

12.
Dalton Trans ; 49(39): 13797-13804, 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33000838

RESUMO

Three novel phosphorescent iridium(iii) complexes with thieno[2,3-d]pyridazine derivatives as cyclometalating chelates were successfully synthesized. These complexes exhibited intense green or yellow phosphorescence emission with short lifetimes of 1.71-1.91 µs and very high quantum yields of over 85% in PMMA films. Even in air-equilibrated CH2Cl2, their quantum yields could be up to 36%. They also showed good thermal stability with Td > 338 °C. The electronic structure information of these complexes was discussed by density functional theory. The tris-cyclometalated complex Ir1 was an excellent yellow phosphorescent dopant for OLED applications, and the maximum CE and PE based on it were 58.5 cd A-1 and 45.9 lm W-1, respectively, with the maximum EQE of 18.2% which was ca. 1.4 times more efficient than that of PO-01. These results indicate that these new complexes have potential applications as efficient phosphors in OLEDs.

13.
Plant Dis ; 2020 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-33044139

RESUMO

Sclerotinia sclerotiorum is one of the most damaging and economically important necrotrophic plant pathogens, infecting more than 400 plant species globally. Although the phenylpyrrole fungicide fludioxonil has high activity against S. sclerotiorum, recent reports have indicated that there is also a substantial potential for the development of fungicide resistance. However, the current study investigating five fludioxonil-resistant laboratory mutants found a significant fitness cost associated with fludioxonil resistance resulting in significantly (p < 0.005) reduced mycelial growth and sclerotia formation on PDA, as well as significantly (p < 0.05) lower pathogenicity on detached tomato leaves, with one mutant, LK-1R, completely losing the capacity to cause infection. In addition, all of the fludioxonil-resistant mutants had significantly (p < 0.05) increased sensitivity to osmotic stress (0.5 M KCl and 1.0 M Glucose), which is consistent with the proposed fludioxonil target sites within the High Osmolarity Glycerol (HOG1) stress response mitogen-activated protein kinase (MAPK) (HOG1-MAPK) signaling transduction pathway. Sequence analysis of six genes from this two-component pathway, including SsHk, SsYpd, SsSk1, SsSk2, SsPbs, and SsHog, revealed several mutations which maybe associated fludioxonil resistance. For example, six separate point mutations were found in the SsHk gene that lead to changes in the predicted amino acid sequence, including A136G, F249V, G353A, E560K, M610K, and K727R. Similarly, the SsPbs gene had three mutations (D34G, S46L, and L337E); the SsSk1 and SsYpd genes two (S53G and A795V, and E67G and Y141H, respectively) and the SsHog and SsSk2 genes one each (V220A and S763P, respectively). To the best of our knowledge, these constitute the first reports of amino acid changes in the proteins of the HOG1-MAPK pathway being associated with fludioxonil resistance in S. sclerotiorum. The study also found a positive cross-resistance between fludioxonil and dimethachlone and procymidone, but none with tebuconazole or carbendazim, indicating that the inclusion of tebuconazole within an integrated pest management program could reduce the risk of fludioxonil developing in field populations of S. sclerotiorum, and ensure the sustainable production of soybeans in China into the future.

14.
Radiology ; : 202261, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33078997

RESUMO

Background The prognostic value of myocardial trabecular complexity in patients with hypertrophic cardiomyopathy (HCM) is unknown. Purpose To explore the prognostic value of myocardial trabecular complexity using fractal analysis in participants with HCM. Materials and Methods The authors prospectively enrolled participants with HCM who underwent 3.0-T cardiovascular MRI from August 2011 to October 2017. The authors also enrolled 100 age- and sex-matched healthy participants to form a comparison group. Trabeculae were quantified with fractal analysis of cine slices to estimate the fractal dimension (FD). Participants with HCM were divided into normal and high FD groups according to the upper limit of normal reference value from the healthy group. The primary end point was defined as all-cause mortality and aborted sudden cardiac death. The secondary end point was the composite of the primary end point and readmission to the hospital owing to heart failure. Internal validation was performed using the bootstrapping method. Results A total of 378 participants with HCM (median age, 50 years; age range, 40-61 years; 207 men) and 100 healthy participants (median age, 46 years; age range, 36-59 years; 55 women) were included in this study. During the median follow-up of 33 months ± 18 (standard deviation), the increased maximal apical FD (≥1.325) had a higher risk of the primary and secondary end points than those with a normal FD (<1.325) (P = .01 and P = .04, respectively). Furthermore, Cox analysis revealed that left ventricular maximal apical FD (hazard ratio range, 1.001-1.008; all P < .05) provided significant prognostic value to predict the primary and secondary end points after adjustment for the European Society of Cardiology predictors and late gadolinium enhancement. Internal validation showed that left ventricular maximal apical FD retained a good performance in predicting the primary end points with an area under the curve of 0.70 ± 0.03. Conclusion Left ventricular apical fractal dimension, which reflects myocardial trabecular complexity, was an independent predictor of the primary and secondary end points in patients with hypertrophic cardiomyopathy. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Captur and Moon in this issue.

15.
Eur J Med Chem ; 209: 112842, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-33065375

RESUMO

Ferroptosis is a new type of programmed cell death discovered recently and has been demonstrated to be involved in a number of human diseases such as ischemic stroke. Ferroptosis inhibitors are expected to have potential to treat these diseases. Herein, we report the identification of promethazine derivatives as a new type of ferroptosis inhibitors. Structure-activity relationship (SAR) analyses led to the discovery of the most potent compound 2-(1-(4-(4-methylpiperazin-1-yl)phenyl)ethyl)-10H-phenothiazine (51), which showed an EC50 (half maximal effective concentration) value of 0.0005 µM in the erastin-induced HT1080 cell ferroptosis model. In the MCAO (middle cerebral artery occlusion) ischemic stroke model, 51 presented an excellent therapeutic effect. This compound also displayed favorable pharmacokinetic properties, in particular, a good ability to permeate the blood-brain barrier. Overall, 51 could be a promising lead compound for the treatment of ferroptosis related diseases and deserves further investigations.

16.
Eur J Anaesthesiol ; 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33074940

RESUMO

BACKGROUND: Previous data show that lidocaine or magnesium has unique characteristics of stress inhibition and antiinflammation. OBJECTIVE: We aimed to observe the effects of lidocaine or magnesium on the quality of recovery (QoR) after laparoscopic cholecystectomy. DESIGN: Single-centre, prospective, randomised, double-blind study. SETTING: The Affiliated Hospital of Xuzhou Medical University from March 2019 to October 2019. PATIENTS: One hundred and fourteen patients scheduled for laparoscopic cholecystectomy. INTERVENTION: The enrolled patients were randomly divided into three groups. Lidocaine (group L), magnesium sulphate (group M) or 0.9% saline (group C) was administered intravenously 10 min before induction. MAIN OUTCOME MEASURES: The quality of recovery 15 (QoR-15) score, the Hospital Anxiety and Depression Scale (HADS), and the Numerical Rating Scale (NRS) score were selected. The usage of propofol and remifentanil, haemodynamic parameters, anaesthesia recovery parameters and adverse events were also evaluated. RESULTS: The QoR-15 scores for group L (132.0) and group M (134.0) were 6 and 8 points higher than that of group C (126.0) on POD1 (postoperative day 1) (adjP < 0.05). However, the decrease of QoR-15 in Group L is less than the minimal clinically important difference (8).The NRS scores on POD1 in group C 3, were higher than other two groups (adjP < 0.05). The dosage of remifentanil in group L was lower than other two groups (adjP < 0.05).The physical independence of group L and group M and physical comfort of group M were improved compared with group C. CONCLUSION: The results show that magnesium sulphate improved the QoR through improving physical comfort and physical independence in patients after laparoscopic cholecystectomy. However, lidocaine had limited effects on QoR under current conditions. TRIAL REGISTRATION: ChiCTR1800019092 (www.chictr.org.cn). CLINICAL TRIAL NUMBER AND REGISTRY URL: The study was registered in the Chinese Clinical Trials Register (ChiCTR1800019092) https://www.chictr.org.cn.

17.
Phys Rev Lett ; 125(12): 128101, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-33016741

RESUMO

The efficiency of a virus to establish its infection in host cells varies broadly among viruses. It remains unclear if there is a key step in this process that controls viral infectivity. To address this question, we use single-particle tracking and Brownian dynamics simulation to examine human immunodeficiency virus type 1 (HIV-1) infection in cell culture. We find that the frequency of viral-cell encounters is consistent with diffusion-limited interactions. However, even under the most favorable conditions, only 1% of the viruses can become immobilized on cell surface and subsequently enter the cell. This is a result of weak interaction between viral surface gp120 and CD4 receptor, which is insufficient to form a stable complex the majority of the time. We provide the first direct quantitation for efficiencies of these events relevant to measured HIV-1 infectivity and demonstrate that immobilization on host cell surface post-virion-diffusion is the key step in viral infection. Variation of its probability controls the efficiency of a virus to infect its host cells. These results explain the low infectivity of cell-free HIV-1 in vitro and offer a potential rationale for the pervasive high efficiency of cell-to-cell transmission of animal viruses.


Assuntos
HIV-1/patogenicidade , Antígenos CD4/metabolismo , Linhagem Celular , Proteína gp120 do Envelope de HIV/metabolismo , HIV-1/metabolismo , Humanos , Imagem Óptica , Imagem com Lapso de Tempo , Vírion/metabolismo , Vírion/patogenicidade
18.
Neurochem Int ; 140: 104845, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32911011

RESUMO

Indole-3-carbinol (I3C), found in cruciferous vegetables, has been proposed to exhibit neuroprotective effects. This study aimed to investigate the effect of the I3C derivative [1(4-chloro-3-nitrobenzenesulfonyl)-1H-indol-3-yl]-methanol (CIM), which has superior pharmacokinetic properties to I3C, on glutamate release in rat cerebrocortical nerve terminals (synaptosomes). We observed that CIM dose-dependently inhibited glutamate release evoked by the potassium channel blocker 4-aminopyridine (4-AP). CIM-mediated inhibition of glutamate release was attributed to reduced exocytosis, as it correlated with the removal of extracellular calcium and blocking of the vesicular glutamate transporter but not the glutamate transporter. In addition, CIM decreased 4-AP-evoked intrasynaptosomal Ca2+ elevation; however, it did not alter the synaptosomal membrane potential. The inhibition of P/Q-typeCa2+ channels abolished the effect of CIM on 4-AP-evoked glutamate release, and the effect was not prevented by intracellular Ca2+ release inhibitors. Moreover, the molecular docking study showed that CIM exhibited the highest binding affinity with the P/Q-type Ca2+channels. Finally, the CIM-mediated inhibition of glutamate release was sensitive to calmodulin, adenylate cyclase (AC), and protein kinase A (PKA) inhibitors. Based on these results, we propose that CIM, through the direct suppression of P/Q-type Ca2+ channels, decreases Ca2+ influx and the activation of Ca2+/calmodulin/AC/PKA signaling, thereby inhibiting glutamate release. This finding is crucial for understanding the role of CIM in the central nervous system and for exploiting its potential in therapeutic interventions.

19.
Anal Methods ; 12(39): 4813-4822, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32966358

RESUMO

Secondary structures in long circulating tumor nucleic acids have potential obstacles for specific location point hybridized detection of gene fragments. The exploration of biosensing strategies requires selectively changing the nucleic acids conformation and inducing signal switching. Herein, a self-assembled magnetic composite probe (MCP) was fabricated by the hybridization reaction of Linker DNA and a "Y"-junction-DNA nanostructure on the surface of magnetic beads, contributing to the capture, secondary structure unlocking, and enrichment of the PML/RARα DNA "L" subtype. Then, by integrating the MCP-actuated reactor, a one-step "off-on" signal switching MoS2@FAM-probe biosensing method was developed for the efficient detection of the PML/RARα DNA "L" subtype. The proposed biosensor was capable of detecting 100 bases PML/RARα DNA "L" subtype with a wide linear range of 1 pM to 200 nM and a limit of detection down to 0.223 pM without signal amplification. In addition, the biosensing method was successfully applied for the detection of target in serum samples. It is worth pointing out that this simple biosensing strategy could enable long nucleic acids fragments with secondary structures from ctDNA and ctRNA to be quantitatively assayed based on direct hybridization.

20.
Sci Rep ; 10(1): 15636, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32973230

RESUMO

Acute kidney disease (AKD) is a state between acute kidney injury (AKI) and chronic kidney disease (CKD), but the prognosis of AKD is unclear and there are no risk-prediction tools to identify high-risk patients. 2,556 AKI patients were selected from 277,898 inpatients of three affiliated hospitals of Central South University from January 2015 to December 2015. The primary point was whether AKI patients developed AKD. The endpoint was death or end stage renal disease (ESRD) 90 days after AKI diagnosis. Multivariable Cox regression was used for 90-day mortality and two prediction models were established by using multivariable logistic regression. Our study found that the incidence of AKD was 53.17% (1,359/2,556), while the mortality rate and incidence of ESRD in AKD cohort was 19.13% (260/1,359) and 3.02% (41/1,359), respectively. Furthermore, adjusted hazard ratio of mortality for AKD versus no AKD was 1.980 (95% CI 1.427-2.747). In scoring model 1, age, gender, hepatorenal syndromes, organic kidney diseases, oliguria or anuria, respiratory failure, blood urea nitrogen (BUN) and acute kidney injury stage were independently associated with AKI progression into AKD. In addition, oliguria or anuria, respiratory failure, shock, central nervous system failure, malignancy, RDW-CV ≥ 13.7% were independent risk factors for death or ESRD in AKD patients in scoring model 2 (goodness-of fit, P1 = 0.930, P2 = 0.105; AUROC1 = 0.879 (95% CI 0.862-0.896), AUROC2 = 0.845 (95% CI 0.813-0.877), respectively). Thus, our study demonstrated AKD was independently associated with increased 90-day mortality in hospitalized AKI patients. A new prediction model system was able to predict AKD following AKI and 90-day prognosis of AKD patients to identify high-risk patients.

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