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1.
Med Sci Monit ; 26: e922139, 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32419697

RESUMO

BACKGROUND Glutamate (GLU) is the most excitatory amino acid in the central nervous system and plays an important role in maintaining the normal function of the nervous system. During cerebral ischemia, massive release of GLU leads to neuronal necrosis and apoptosis. It has been reported that dexmedetomidine (DEX) possesses anti-oxidant and anti-apoptotic properties. The objective of this study was to investigate the effects of DEX on GLU-induced neurotoxicity in PC12 cells. MATERIAL AND METHODS PC12 cells were treated with 20 mM GLU to establish an ischemia-induced injury model. Cell viability was accessed by MTT assay. MDA content and SOD activity were analyzed by assay kits. Apoptosis rate, ROS production, intracellular Ca²âº concentration, and MMP were evaluated by flow cytometry. Western blot analysis was performed to analyze expressions of caspase-3, caspase-9, cyt-c, bax, and bcl-2. RESULTS PC12 cells treated with GLU exhibited reduced cell viability and increased apoptosis rates, which were ameliorated by pretreatment with DEX. DEX significantly increased SOD activity, reduced content of MDA, and decreased production of ROS in PC12 cells. In addition, DEX clearly reduced the level of intracellular Ca²âº and attenuated the decline of MMP. Moreover, DEX notably reduced expressions of caspase-3, caspase-9, cyt-c, and bax and increased expression of bcl-2. CONCLUSIONS Our findings suggest that DEX can protect PC12 cells against GLU-induced cytotoxicity, which may be attributed to its anti-oxidative property and reduction of intracellular calcium overload, as well as its ability to inhibit the mitochondria-mediated apoptotic pathway.

2.
Materials (Basel) ; 13(9)2020 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-32357507

RESUMO

Arc discharge is traditionally used to synthesize randomly arranged graphene flakes. In this paper, we substantially modify it into a glow discharge method so that the discharge current is much more reduced. The H2 and/or Ar plasma etching of the graphitic electrode (used to ignite the plasma) is hence much gentler, rendering it possible to grow graphene in thin film format. During the growth at a few mbar, there is no external carbon gas precursor introduced. The carbon atoms and/or carbon containing particles as a result of the plasma etching are emitted in the chamber, some of which undergo gas phase scattering and deposit onto the metallic catalyst substrates (Cu-Ni alloy thin films or Cu foils) as graphene sheets. It is found that high quality monolayer graphene can be synthesized on Cu foil at 900 °C. On Cu-Ni, under the same growth condition, somewhat more bilayer regions are observed. It is observed that the material quality is almost indifferent to the gas ratios, which makes the optimization of the deposition process relatively easy. Detailed study on the deposition procedure and the material characterization have been carried out. This work reveals the possibility of producing thin film graphene by a gas discharge based process, not only from fundamental point of view, but it also provides an alternative technique other than standard chemical vapor deposition to synthesize graphene that is compatible with the semiconductor planar process. As the process uses solid graphite as a source material that is rich in the crust, it is a facile and relatively cheap method to obtain high quality graphene thin films in this respect.

3.
Bioorg Chem ; 100: 103873, 2020 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-32361294

RESUMO

Carbapenem-resistant Enterobacteriaceae (CRE) producing New Delhi metallo-ß-lactamase (NDM-1) cause untreatable bacterial infections, posing a significant threat to human health. In the present study, by employing the concept of bioisosteric replacement of the selenium moiety of ebselen, we have designed, synthesized and characterized a small compound library of 2-substituted 1,2-benzisothiazol-3(2H)-one derivatives and related compounds for evaluating their cytotoxicity and synergistic activity in combination with meropenem against the E. coli Tg1 (NDM-1) strain. The most promising compound 3a demonstrated potent synergistic activity against a panel of clinically isolated NDM-1 positive CRE strains with FICI as low as 0.09. Moreover, its IC50 value and inhibition mechanism were also confirmed by using the enzyme inhibition assay and the ESI-MS analysis respectively. Importantly, compound 3a has acceptable toxicity and is not a PAINS. Because of its structural simplicity and potent synergistic activity in combination with meropenem, we propose that compound 3a may be a promising meropenem adjuvant and a new series of such compounds may worth further investigations.

4.
Eur Respir J ; 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32366484

RESUMO

It is currently not understood whether cigarette smoke (CS) exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive COPD-associated pathologies.To address this question, mice were exposed to CS for 2 weeks. Following a two-week period of rest, mice were challenged intratracheally with elastin for 3 days or 1 month. Rag1-/- , Mmp12-/- , and Il17a-/- mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2 weeks of CS exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodelling, lung function decline, and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adoptive T cell transfer and studies in T cells deficient Rag1-/- mice conclusively implicated T cells in these processes. Mechanistically, CS exposure induced elastin-specific T cell responses were MMP12-dependent, while the ensuing immune inflammatory processes were IL17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the CS-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of CS-induced autoimmune processes and may serve as a novel mouse model of COPD.

5.
Anal Chem ; 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32395992

RESUMO

Caspase-3 is considered as one of the key proteases that can spontaneously regulate the life activities of cells, and its activation (usually is a slow process) will execute the apoptosis process of cells. Rapid activation of caspase-3 on demand in living-cells is therefore highly desired toward precise cancer therapy but it is still a key challenge. Herein, we applied electrostimulus (ES) to achieve fast activation of caspase-3 and trigger cell apoptosis, and developed a smart magnetic-plasmonic assembly nanoprobes (A-nanoprobes) to real-time trace cellular caspase-3 activation at the single cell level. The designer core-satellite A-nanoprobe, working specific to the activated caspase-3 via a disassembly tactic, provides strong "hot spots" to improve the sensitivity and therefore enables SERS sensing of cellular caspase-3 upon activated by ES. Single-cell analysis revealed that the ES can rapidly activate the apoptosis pathway of caspase-3 on demand to make the DNA fragmentation and ultimately induce the cell apoptosis. Such method and nanoplatform were further used to monitor ES-triggered caspase-3 activation in cell apoptosis process of different cell types, revealing that more caspase-3 will be activated for cancerous cells than normal cells during the ES to induce cells apoptosis. This strategy and platform are promising for detecting cellular caspase-3 and other enzymes in the process of cancer diagnosis and treatments.

6.
Nat Commun ; 11(1): 2490, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427821

RESUMO

Non-Markovian spontaneous recovery processes with a time delay (memory) are ubiquitous in the real world. How does the non-Markovian characteristic affect failure propagation in complex networks? We consider failures due to internal causes at the nodal level and external failures due to an adverse environment, and develop a pair approximation analysis taking into account the two-node correlation. In general, a high failure stationary state can arise, corresponding to large-scale failures that can significantly compromise the functioning of the network. We uncover a striking phenomenon: memory associated with nodal recovery can counter-intuitively make the network more resilient against large-scale failures. In natural systems, the intrinsic non-Markovian characteristic of nodal recovery may thus be one reason for their resilience. In engineering design, incorporating certain non-Markovian features into the network may be beneficial to equipping it with a strong resilient capability to resist catastrophic failures.

7.
Biomaterials ; 248: 120031, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32283391

RESUMO

Multimodal therapy has been continuously explored for different diseases. Photodynamic/gene combined therapy is a promising treatment strategy of tumor. However, the limitation of traditional chemical photosensitizer and the asynchronism of the two therapies restrict the development of this technology. Herein, one genetically multimodal treatment nanosystem (HES@PGEA/pKR-p53), composed of biocompatible hydroxyethyl starch (HES), low-toxic ß-cyclodextrin-based ethanolamine-functionalized poly(glycidyl methacrylate) (CD-PGEA) and combined plasmid pKR-p53, is structurally designed based on host-guest assembly and electrostatic complexing. Supramolecular assembled HES@PGEA exhibits low cytotoxicity, excellent cellular internalization and enhanced gene transfection efficiency. With the delivery of pKR-p53, p53 and KillerRed proteins could be expressed simultaneously in the same tumor cell for p53-mediated apoptosis therapy and photodynamic therapy (PDT), where the synergistic effect of KillerRed and p53 proteins is achieved. Compared with single therapy, HES@PGEA/pKR-p53 shows more remarkable antitumor effects in the 4T1 tumor model.

8.
Mol Oncol ; 2020 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-32335998

RESUMO

Linc-ROR is reported to be a potential biomarker of breast cancer, but the detailed mechanism of linc-ROR-mediated breast cancer regulation has not been fully studied. We aimed to explore how linc-ROR affects proliferation, metastasis and drug sensitivity in breast cancer. Cell lines in which linc-ROR was overexpressed or knocked down were constructed, and the cell proliferation, colony formation, cell migration and invasion abilities of these lines were explored. A CCK-8 assay was performed to determine the sensitivity of the breast cancer cells to rapamycin. Next-generation sequencing was conducted to explore the detailed regulatory mechanism of linc-ROR; differentially expressed RNAs in the linc-ROR-overexpressing cell line compared with the negative control were screened out and their target genes were chosen to perform Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, protein-protein interaction (PPI) network analysis and competing endogenous RNA (ceRNA) network analysis. The ceRNA mechanism of linc-ROR for miR-194-3p, which targets MECP2, was determined through dual-luciferase reporter assay, RT-qPCR, western blot and rescue experiments. Finally, we found that linc-ROR was upregulated in breast tumor tissues. Linc-ROR promoted the cell proliferation, colony formation, cell migration and invasion of breast cancer and decreased the sensitivity of breast cancer cells to rapamycin. The overexpression of linc-ROR triggered changes in the whole transcriptome of breast cancer cells, and a total of 85 lncRNAs, 414 microRNAs, 490 mRNAs and 92 circRNAs were differentially expressed in the linc-ROR-overexpressing cell line compared with the negative control. Through a series of bioinformatics analyses, the "linc-ROR/miR-194-3p/MECP2" ceRNA regulatory axis was confirmed to be involved in the linc-ROR-mediated progression and drug sensitivity of breast cancer. In conclusion, linc-ROR serves as an onco-lncRNA in breast cancer and promotes the survival of breast cancer cells during rapamycin treatment by functioning as a ceRNA sponge for miR-194-3p, which targets MECP2.

9.
Front Med ; 14(2): 199-209, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32279219

RESUMO

The outbreak of the coronavirus disease 2019 was first reported in Wuhan in December 2019 and gradually spread to other areas in China. After implementation of prevention and control measures, the estimation of the epidemic trend is needed. A phase- and region-adjusted SEIR model was applied for modeling and predicting the number of cases in Wuhan, Hubei Province and regions outside Hubei Province in China. The estimated number of infections could reach its peak in late February 2020 in Wuhan and Hubei Province, which is 55 303-84 520 and 83 944-129 312, respectively, while the epidemic peaks in regions outside Hubei Province in China could appear on February 13, 2020 with the estimated 13 035-19 108 cases. According to the estimation, the outbreak would abate in March and April all over China. Current estimation provided evidence for planned work resumption under stringent prevention and control in China to further support the fight against the epidemic. Nevertheless, there is still possibility of the second outbreak brought by the work resumption and population migration, especially from Hubei Province and high intensity cities outside Hubei Province. Strict prevention and control measures still need to be considered in the regions with high intensity of epidemic and densely-populated cities.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Epidemias , Pneumonia Viral/epidemiologia , China/epidemiologia , Humanos , Pandemias , Estatística como Assunto
10.
Chem Commun (Camb) ; 2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32323669

RESUMO

We report on a supramolecular sensor array using fluorogenic peptide probes and graphene oxide that can target glycoproteins on a viral caspid, facilitating the differentiation of ebola virus from marburg virus and receptor-extensive vesicular stomatitis virus using principal component analysis.

11.
Anal Chim Acta ; 1111: 1-7, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32312386

RESUMO

In this work, a novel homogeneous electrochemical aptasensor based on electrically assisted bond and tetraferrocene signal amplification was constructed for thrombin detection. Importantly, modification of the electrode is not necessary for this sensor, requiring only the construction of a simple and efficient probe. In addition, a brand new signal marker-tetraferrocene, containing four ferrocene molecules, was employed as a label to the terminal position of the probe. Compared with a single ferrocene moiety, tetraferrocene possesses a larger amplification signal for rapid detection of thrombin. In the detection of thrombin, the selected aptamer probe with a stem-loop structure was labeled with tetraferrocene at the 3' terminal and thiol at the 5' terminal, respectively. Confinement of the thiol to the stem-loop structure of the probe, the ability of thiol to reach the surface of electrode lossed even with the aid of the applied potential. However, upon treatment with the target protein of thrombin the stem-loop structure opened, promoting rapid attachment of the thiol group to the electrode interface generating Au-S self-assembly with the action of potential-assistance. The electrochemical signal of tetraferrocene could be measured by differential pulse voltammetry (DPV), which was subsequently used for target quantitative detection. This strategy displayed a detection limit as low as 0.126 pM, and an inherently high specificity for the detection of a single mismatch. Moreover, it exhibited advanced specificity against common interfering proteins.

12.
Protein Cell ; 2020 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-32277346

RESUMO

Dysregulation of circadian rhythms associates with cardiovascular disorders. It is known that deletion of the core circadian gene Bmal1 in mice causes dilated cardiomyopathy. However, the biological rhythm regulation system in mouse is very different from that of humans. Whether BMAL1 plays a role in regulating human heart function remains unclear. Here we generated a BMAL1 knockout human embryonic stem cell (hESC) model and further derived human BMAL1 deficient cardiomyocytes. We show that BMAL1 deficient hESC-derived cardiomyocytes exhibited typical phenotypes of dilated cardiomyopathy including attenuated contractility, calcium dysregulation, and disorganized myofilaments. In addition, mitochondrial fission and mitophagy were suppressed in BMAL1 deficient hESC-cardiomyocytes, which resulted in significantly attenuated mitochondrial oxidative phosphorylation and compromised cardiomyocyte function. We also found that BMAL1 binds to the E-box element in the promoter region of BNIP3 gene and specifically controls BNIP3 protein expression. BMAL1 knockout directly reduced BNIP3 protein level, causing compromised mitophagy and mitochondria dysfunction and thereby leading to compromised cardiomyocyte function. Our data indicated that the core circadian gene BMAL1 is critical for normal mitochondria activities and cardiac function. Circadian rhythm disruption may directly link to compromised heart function and dilated cardiomyopathy in humans.

13.
Clin Lab ; 66(4)2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32255308

RESUMO

BACKGROUND: Infections account for considerable morbidity and mortality in end stage renal disease (ESRD) patients. Serum procalcitonin (PCT) is used in the early diagnosis of bacterial infection and has higher sensitivity and specificity. However, the level of PCT might be affected. METHODS AND RESULTS: We reported an ESRD patient with abnormal liver function manifesting a high level of serum PCT. The evidence of infection was not found, and with the constant adjustment of antibiotic therapy, the level of PCT remained high. However, the PCT level gradually recovered after discontinuing all antibiotic therapy. The correlative analysis suggested a strong positive correlation between PCT and TBIL and DBIL. CONCLUSIONS: Without the evidence of infection, PCT could be affected by liver function. When an ESRD patient with abnormal liver function manifested a high level of PCT, the influence of liver function especially bilirubin on PCT should be considered.

14.
Artigo em Inglês | MEDLINE | ID: mdl-32305896

RESUMO

Tensor Principal Component Pursuit (TPCP) is a powerful approach in the Tensor Robust Principal Component Analysis (TRPCA), where the goal is to decompose a data tensor to a low-tubal-rank part plus a sparse residual. TPCP is shown to be effective under certain tensor incoherence conditions, which can be restrictive in practice. In this paper, we propose a Modified-TPCP, which incorporates the prior subspace information in the analysis. With the aid of prior info, the proposed method is able to recover the low-tubal-rank and the sparse components under a significantly weaker incoherence assumption. We further design an efficient algorithm to implement Modified-TPCP based upon the Alternating Direction Method of Multipliers (ADMM). The promising performance of the proposed method is supported by simulations and real data applications.

15.
Chem Commun (Camb) ; 56(40): 5393-5396, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32285901

RESUMO

A cytochrome c (Cyt c)-modified glass nanopore sensing platform was constructed to sensitively detect glucose in single cells based on changes in the ionic current rectification (ICR) of the system. A difference in glucose content between single H8 and HeLa cells in their satiety or starvation states was clearly able to be detected using this method.

16.
Bioorg Chem ; 99: 103824, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32334192

RESUMO

The chemokine receptor CXCR4 has been explored as a drug target due to its involvement in pathological conditions such as HIV infection and cancer metastasis. Here we report the structure-activity relationship study of novel CXCR4 antagonists based on an aminoquinoline template. This template is devoid of the chiral center in the classical tetrahydroquinoline (THQ) ring moiety and therefore can be easily synthesized. A number of potent CXCR4 antagonists were identified, exemplified by compound 3, which demonstrated excellent binding affinity with CXCR4 receptor (IC50 = 57 nM) and inhibited CXCL12 induced cytosolic calcium increase (IC50 = 0.24 nM). Furthermore, compound 3 potently inhibited CXLC12/CXCR4 mediated cell migration in a transwell invasion assay. The simplified synthetic approach combined with good physicochemical properties (e.g. MW 362, clogP 2.1, PSA 48, pKa 7.0 for compound 3) demonstrate the potential of this aminoquinoline template as a novel scaffold to develop CXCR4 antagonists.

17.
Bioorg Chem ; 99: 103838, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32334194

RESUMO

A series of novel pyrazoline derivatives containing methyl-1H-indole moiety were discovered as potential inhibitors for blocking APC-Asef interactions. The top hit Q19 suggested potency of inhibiting APC-Asef interactions and attractive preference for human-sourced colorectal cells. It was already comparable with the previous representative and the positive control Regorafenib before further pharmacokinetic optimization. The introduction of methyl-1H-indole moiety realized the Mitochondrial affection thus might connect the impact on the protein-interaction level with the apoptosis events. The molecular docking simulation inferred that bringing trifluoromethyl groups seemed a promising approach for causing more key interactions such as H-bonds. This work raised referable information for further discovery of inhibitors for blocking APC-Asef interactions.

18.
Front Med ; 14(2): 215-219, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32212059

RESUMO

The world must act fast to contain wider international spread of the epidemic of COVID-19 now. The unprecedented public health efforts in China have contained the spread of this new virus. Measures taken in China are currently proven to reduce human-to-human transmission successfully. We summarized the effective intervention and prevention measures in the fields of public health response, clinical management, and research development in China, which may provide vital lessons for the global response. It is really important to take collaborative actions now to save more lives from the pandemic of COVID-19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , China/epidemiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/terapia , Infecções por Coronavirus/transmissão , Humanos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/terapia , Pneumonia Viral/transmissão , Saúde Pública
19.
Reproduction ; 159(6): 733-743, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32213653

RESUMO

Some studies have demonstrated that the implantation rate of fresh transfer cycles is lower in the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol than in the GnRH agonist (GnRH-a) protocol during in vitro fertilization (IVF). This effect may be related to endometrial receptivity. However, the mechanisms are unclear. Here, endometrial tissues obtained from the mid-secretory phase of patients treated with GnRH-a or GnRH-ant protocols and from patients on their natural cycle were assessed. Endometrial expression of B-type creatine kinase (CKB), which plays important roles in the implantation phase, was significantly reduced in the GnRH-ant group. At the same time, expression of the endometrial receptivity marker HOXA10 was considerably reduced in the GnRH-ant group. GnRH-ant exposure in endometrial epithelial cells (EECs) in vitro decreased CKB expression and ATP generation and blocked polymerization of actin. Furthermore, in vitro GnRH-ant-exposed Ishikawa cells showed enhanced F-actin depolymerization, and these effects were rescued by CKB overexpression. Similar effects were observed after CKB knockdown, and these effects were rescued by CKB overexpression. Moreover, cell migration was decreased in CKB-knockdown Ishikawa cells compared with that in control cells, and this effect was also rescued by CKB overexpression. Overall, these findings showed that GnRH-ant affected CKB expression in EECs, resulting in cytoskeletal damage and migration failure. These results provide insight into the roles and molecular mechanisms of GnRH-ant treatment in the endometrium.

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