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1.
Arch Physiol Biochem ; : 1-9, 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33950771

RESUMO

Exosomes are a kind of nanoscale extracellular vesicles with diameters of 30-100 nm and act as intracellular communication vehicles to influence cellular activities. Emerging pieces of evidence have indicated that exosomes play important roles in inflammation. However, the biological roles of plasma exosomes in acute myocardial infarction (AMI) patients have remained largely unexplored. In the current study, we found the plasma exosome levels were notably increased in patients with AMI in comparison with healthy controls (HCs), and AMI exosomes could induce endothelial cell injury. Furthermore, our data demonstrated that AMI exosomes triggered a pro-inflammatory immune response, at least partly depending on the activation of the NF-ĸB signalling. Together, AMI exosomes have pro-inflammatory properties and play a significant role in inflammation in AMI patients.

2.
Theranostics ; 11(12): 5794-5812, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897882

RESUMO

Rationale: Resistance to androgen-deprivation therapy (ADT) associated with metastatic progression remains a challenging clinical task in prostate cancer (PCa) treatment. Current targeted therapies for castration-resistant prostate cancer (CRPC) are not durable. The exact molecular mechanisms mediating resistance to castration therapy that lead to CRPC progression remain obscure. Methods: The expression of MYB proto-oncogene like 2 (MYBL2) was evaluated in PCa samples. The effect of MYBL2 on the response to ADT was determined by in vitro and in vivo experiments. The survival of patients with PCa was analyzed using clinical specimens (n = 132) and data from The Cancer Genome Atlas (n = 450). The mechanistic model of MYBL2 in regulating gene expression was further detected by subcellular fractionation, western blotting, quantitative real-time PCR, chromatin immunoprecipitation, and luciferase reporter assays. Results: MYBL2 expression was significantly upregulated in CRPC tissues and cell lines. Overexpression of MYBL2 could facilitate castration-resistant growth and metastatic capacity in androgen-dependent PCa cells by promoting YAP1 transcriptional activity via modulating the activity of the Rho GTPases RhoA and LATS1 kinase. Importantly, targeting MYBL2, or treatment with either the YAP/TAZ inhibitor Verteporfin or the RhoA inhibitor Simvastatin, reversed the resistance to ADT and blocked bone metastasis in CRPC cells. Finally, high MYBL2 levels were positively associated with TNM stage, total PSA level, and Gleason score and predicted a higher risk of metastatic relapse and poor prognosis in patients with PCa. Conclusions: Our results reveal a novel molecular mechanism conferring resistance to ADT and provide a strong rationale for potential therapeutic strategies against CRPC.

3.
Cell Death Dis ; 12(4): 336, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33795653

RESUMO

The tumor necrosis factor (TNF) receptor superfamily member 11a (TNFRSF11a, also known as RANK) was demonstrated to play an important role in tumor metastasis. However, the specific function of RANK in colorectal cancer (CRC) metastasis and the underlying mechanism are unknown. In this study, we found that RANK expression was markedly upregulated in CRC tissues compared with that in matched noncancerous tissues. Increased RANK expression correlated positively with metastasis, higher TNM stage, and worse prognosis in patients with CRC. Overexpression of RANK promoted CRC cell metastasis in vitro and in vivo, while knockdown of RANK decreased cell migration and invasion. Mechanistically, RANK overexpression significantly upregulated the expression of tartrate-resistant acid phosphatase 5 (TRAP/ACP5) in CRC cells. Silencing of ACP5 in RANK-overexpressing CRC cells attenuated RANK-induced migration and invasion, whereas overexpression of ACP5 increased the migration and invasion of RANK-silencing cells. The ACP5 expression was transcriptionally regulated by calcineurin/nuclear factor of activated T cells c1 (NFATC1) axis. The inhibition of calcineurin/NFATC1 significantly decreased ACP5 expression, and attenuated RANK-induced cell migration and invasion. Furthermore, RANK induced phospholipase C-gamma (PLCγ)-mediated inositol-1,4,5-trisphosphate receptor (IP3R) axis and stromal interaction molecule 1 (STIM1) to evoke calcium (Ca2+) oscillation. The RANK-mediated intracellular Ca2+ mobilization stimulated calcineurin to dephosphorylate NFATC1 and induce NFATC1 nuclear translocation. Both blockage of PLCγ-IP3R axis and STIM1 rescued RANK-induced NFATC1 nuclear translocation, ACP5 expression, and cell metastasis. Our study revealed the functional expression of RANK in human CRC cells and demonstrated that RANK induced the Ca2+-calcineurin/NFATC1-ACP5 axis in the regulation of CRC metastasis, that might be amenable to therapeutic targeting.

4.
J Hazard Mater ; 414: 125395, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33652218

RESUMO

Developing a novel core-multishelled metal oxide hollow tube with rich oxygen vacancy is highly attractive in photocatalytic degradation of antibiotic pollutant. Herein, ZnO@In2O3 core-shell hollow microtubes were synthesized via one-step calcination of ZIF-8@MIL-68(In) formed by an in-situ self-assembly. TEM images demonstrate that 0D ZnO quantum dots (QDs) shell with 0.2 µm were well coated on the surface of 1D In2O3 hollow tube as the core with 1.2 µm. The synthesized heterostructure indicates the enhanced photocatalytic performance in tetracycline (TC) degradation compared with single ZIF-derived ZnO and MIL-68(In)-derived In2O3 under simulated solar irradiation. Besides, organic pollutants including malachite green (MG), methylene blue (MB) and rhodamine B (RhB) are further used to evaluate the photocatalytic activity of ZnO@In2O3, and the effect of weight ratios between ZnO and In2O3 on degradation efficiency is also studies. The ZnO@In2O3 heterojunction can provide higher specific surface area, expose more active sites, possess appropriate number of oxygen vacancies, enhance light absorption and further effectively boost the transfer and separation of photoinduced charge carriers. In addition, the proposed photocatalytic mechanism and degradation pathway are discussed in detail based on active species trapping test, electron spin resonance (ESR) and LCMS.

5.
Chemosphere ; 271: 129827, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33736215

RESUMO

A 3D porous sponge based on amino-terminated polydimethylsiloxane (PDMS) and graphene oxide (GO) was prepared using a simple one-pot method under mild conditions. Condensing agents combined GO and PDMS with covalent bonds, and simultaneously acted as the pore-foaming agents. Scanning electron microscopy and Mercury intrusion porosimetry revealed that the joint action of GO and condensing agents contributes to the formation of the porous structure. Cyclic compression demonstrated high toughness and elasticity. No deformation occurs after 20 compression cycles at over 80% strain, owing to the assistance of dynamic hydrogen bonds. GO content significantly influences the mechanical strength, hydrophobicity, as well as adsorption capacity for oil. Notably, the sponge can be repeatedly used with a simple squeezing method, and the adsorption capacity can still reach 96.30% of the first adsorption after 30 cycles of adsorption. Besides, the sponge was used to adsorb oil on the seawater surface experimentally. The stable structure, high mechanical strength, and excellent adsorption property suggest the sponge be a promising material for the treatment of oil leakage and oily wastewater purification in practice. This self-foaming method can be a common method for fabricating porous and stable porous materials.


Assuntos
Purificação da Água , Adsorção , Dimetilpolisiloxanos , Óleos , Água
6.
Med Sci Monit ; 27: e928366, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33741890

RESUMO

BACKGROUND Atrial fibrillation (AF) is the most prevalent arrhythmia worldwide. Although it is not life-threatening, the accompanying rapid and irregular ventricular rate can lead to hemodynamic deterioration and obvious symptoms, especially the risk of cerebrovascular embolism. Our study aimed to identify novel and promising genes that could explain the underlying mechanism of AF development. MATERIAL AND METHODS Expression profiles GSE41177, GSE79768, and GSE14975 were acquired from the Gene Expression Omnibus Database. R software was used for identifying differentially expressed genes (DEGs), and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were subsequently performed. A protein-protein interaction network was constructed in Cytoscape software. Next, a least absolute shrinkage and selection operator (LASSO) model was constructed and receiver-operating characteristic curve analysis was conducted to assess the specificity and sensitivity of the key genes. RESULTS We obtained 204 DEGs from the datasets. The DEGs were mostly involved in immune response and cell communication. The primary pathways of the DEGs were related to the course or maintenance of autoimmune and chronic inflammatory diseases. The top 20 hub genes (high scores in cytoHubba) were selected in the PPI network. Finally, we identified 6 key genes (FCGR3B, CLEC10A, FPR2, IGSF6, S100A9, and S100A12) via the LASSO model. CONCLUSIONS We present 6 target genes that are potentially involved in the molecular mechanisms of AF development. In addition, these genes are likely to serve as potential therapeutic targets.

7.
BMC Genomics ; 22(1): 210, 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33761872

RESUMO

BACKGROUND: Safety issues of probiotic products have been reported frequently in recent years. Ten bacterial strains isolated from seven commercial probiotic products on market were evaluated for their safety, by whole-genome analysis. RESULTS: We found that the bacterial species of three probiotic products were incorrectly labeled. Furthermore, six probiotic product isolates (PPS) contained genes for the production of toxic metabolites, while another three strains contained virulence genes, which might pose a potential health risk. In addition, three of them have drug-resistance genes, among which two strains potentially displayed multidrug resistance. One isolate has in silico predicted transferable genes responsible for toxic metabolite production, and they could potentially transfer to human gut microflora or environmental bacteria. Isolates of Lactobacillus rhamnosus and Bifidobacterium animalis subsp. lactis are associated with low risk for human consumption. Based on a comparative genome analysis, we found that the isolated Enterococcus faecium TK-P5D clustered with a well-defined probiotic strain, while E. faecalis TK-P4B clustered with a pathogenic strain. CONCLUSIONS: Our work clearly illustrates that whole-genome analysis is a useful method to evaluate the quality and safety of probiotic products. Regulatory quality control and stringent regulations on probiotic products are needed to ensure safe consumption and protect human health.

8.
Cancer Biol Ther ; : 1-11, 2020 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-33280497

RESUMO

PROBLEM AND AIM: The overexpression of MAP17 has been reported in various human carcinomas. However, its molecular mechanism in non-small cell lung cancer (NSCLC) has not been fully understood. Our study aimed to reveal the molecular mechanism of NSCLC that involved MAP17 and identify its target miRNA. METHODS: RT-qPCR and immunoblot assays were conducted to measure the expression of mRNA and protein in NSCLC tissues and cell lines. Meanwhile, the A549 cells (an NSCLC cell line) were randomly assigned to the MAP17 overexpression group, the MAP17 knockdown group and negative control group to study the roles of MAP17 in cell viability, cell proliferation, migration, invasion, and apoptosis by performing Trypan blue exclusion, MTT, colony formation, transwell, wound healing and flow-cytometric apoptosis assays. The luciferase reporter assay was conducted to confirm the target relationship between MAP17 and miR-27a-3p. RESULTS: The upregulation of MAP17 mRNA and protein was observed in NSCLC tissues and cell lines. In vitro, the positive roles of MAP17 on cell viability, migration, and invasion were confirmed in A549 cells. It was also found that MAP17 could inhibit cell apoptosis by suppressing the activation of the p38 pathway. This research eventually proved the target relationship between MAP17 and miR-27a-3p, and that miR-27a-3p reversed the effects of MAP17 in A549 cells by directly targeting MAP17. CONCLUSIONS: MAP17 plays an oncogenic role in NSCLC by suppressing the activation of the p38 pathway. Apart from that, the miR-27a-3p can inhibit the expression of MAP17 to suppress the NSCLC progression.

9.
Bioinformatics ; 2020 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-33270826

RESUMO

SUMMARY: Sampling of control variants having matched properties with input variants is widely used in enrichment analysis of genome-wide association studies/quantitative trait loci and negative data construction for pathogenic/regulatory variant prediction methods. Spurious enrichment results because of confounding factors, such as minor allele frequency and linkage disequilibrium pattern, can be avoided by calibration of statistical significance based on matched controls. Here, we presented vSampler which can generate sets of randomly drawn variants with comprehensive choices of matching properties, such as tissue/cell type-specific epigenomic features. Importantly, the development of a novel data structure and sampling algorithms for vSampler makes it significantly fast than existing tools. AVAILABILITY AND IMPLEMENTATION: vSampler web server and local program are available at http://mulinlab.org/vsampler. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

10.
Dig Dis ; 2020 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-33316803

RESUMO

INTRODUCTION: ACP5 plays crucial roles in multiple pathological processes, including the genesis and progression of malignant tumors. We performed this study with the purpose of determining whether ACP5 is a crucial biomarker significantly related with prognoses of gastric cancer (GC) patients. METHODS: The expression level of ACP5 level was assessed among 170 gastric cancer specimens using immunohistochemistry (IHC). The associations between ACP5 expression and clinicopathological variables were evaluated. Univariate and multivariate Cox regression analyses were performed to confirm independent prognostic factors for GC patients. RESULTS: It was revealed that ACP5 expression level in gastric cancer tissue was significantly associated with depth of invasion (P=0.029), and TNM stage (P=0.036). ACP5 was demonstrated by multivariate Cox regression analysis to be an independent prognostic factor for overall survival (OS) (P=0.001) and recurrence-free survival (RFS) (P=0.011) of GC patients. CONCLUSIONS: The expression of ACP5 in GC tissue was significantly higher than that in normal tissues and its overexpression was associated with a poorer prognosis, suggesting its potential roles in preventing and treating GC.

11.
BMC Pregnancy Childbirth ; 20(1): 735, 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33243171

RESUMO

BACKGROUND: Mothers with hypertensive disorder of pregnancy can be managed with either immediate or delayed induction of labour with expectant monitoring of both mother and baby. There are risks and benefits associated with both the type of interventions. Hence, this review was conducted to compare outcomes of immediate and delayed induction of labour among women with hypertensive disorder of pregnancy based on disease severity and gestational age. METHODS: We conducted systematic searches in various databases including Medline, Cochrane Controlled Register of Trials (CENTRAL), Scopus, and Embase from inception until October 2019.Cochrane risk of bias tool was used to assess the quality of published trials. A meta-analysis was performed with random-effects model and reported pooled Risk ratios (RR) with 95% confidence intervals (CIs). RESULTS: Fourteen randomized controlled trials with 4244 participants were included. Majority of the studies had low or unclear bias risks. Amongst late onset mild pre-eclampsia patients, the risk of renal failure was significantly lower with immediate induction of labour (pooled RR: 0.36; 95%CI: 0.14 to 0.92). In severe pre-eclampsia patients, immediate induction of labour significantly reduced the risk of having small-for-gestational age babies compared to delayed induction of labour (pooled RR: 0.49; 95%CI: 0.29-0.84).Delayed induction was found to significantly reduce the risk of neonatal respiratory distress syndrome risk among late onset mild pre-eclampsia patients (pooled RR: 2.15; 95%CI: 1.14 to 4.06) None of the other outcomes demonstrated statistically significant difference between the two interventions. CONCLUSION: Delayed induction of labour with expectant monitoring may not be inferior to immediate induction of labour in terms of neonatal and maternal outcomes. Expectant approach of management for late onset mild pre-eclampsia patients may be associated with decreased risk of neonatal respiratory distress syndrome, while immediate induction of labour among severe pre-eclampsia patients is associated with reduced risk of small-for-gestational age babies and among mild pre-eclampsia patients, it is associated with reduced risk of severe renal impairment.

12.
Shanghai Kou Qiang Yi Xue ; 29(3): 225-230, 2020 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-33043336

RESUMO

PURPOSE: To investigate the effects of exendin-4(EX-4) on proliferation, migration and osteogenic differentiation of human periodontal ligament stem cells(PDLSCs). METHODS: PDLSCs were isolated and cultured using limited dilution method in vitro. Colony formation assay, osteogenic and adipogenic differentiation were applied to identify the stem cells. Immunofluorescence staining was used to detect the expression of EX-4 receptor glucagon-like peptide-1 receptor (GLP-1R) on the surface of PDLSCs. PDLSCs were stimulated with 5, 10, 20 or 50 nmol/L EX-4 in vitro. CCK-8, Transwell assay and alkaline phosphatase(ALP) activity assay were used to determine the effects of EX-4 on PDLSCs proliferation, migration and osteogenic differentiation. Quantitative real-time polymerase chain reaction was used to determine the expression of osteogenic related genes ALP, runt-related transcription factor 2(Runx2) and osteocalcin (OCN). The data were analyzed by Graphpad Prims 6.0 software package. RESULTS: PDLSCs were successfully isolated and cultivated. GLP-1R positively expressed on the surface of PDLSCs. EX-4 exerted no significant effect on PDLSCs proliferation(P>0.05). EX-4 significantly promoted migration, ALP activity and osteogenic related genes expression of PDLSCs (P<0.05). CONCLUSIONS: 10 nmol/L EX-4 could promote migration and osteogenic differentiation of PDLSCs.


Assuntos
Exenatida , Ligamento Periodontal , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Exenatida/farmacologia , Humanos , Osteogênese , Células-Tronco
13.
J Food Biochem ; 44(11): e13462, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32954518

RESUMO

Colorectal cancer, the most common malignancy in Asian and west world, is listed as the fourth lethal neoplastic disease with increasing incidence worldwide. Recently, Ziziphus jujube were reported with hepatoprotective, antihypertensive, and hypoglycemic functions. The polysaccharides from Ziziphus jujube was considered as the main component for these bioactivities. In this study, polysaccharides from Ziziphus jujube cv. Goutouzao (GZSP) was comprehensively investigated, and characterized as a heteropolysaccharide with antioxidant activity. Besides, it can stimulate the viability of immune cells RAW 264.7, which in turn inhibited the proliferation of colorectal carcinoma cells (LoVo) by inducing apoptosis, arresting cell cycle in G0/G1, and increasing intracellular ROS, as demonstrated by Flow Cytometric analyses. The results suggest that, different from chemotherapeutic modalities, GZSP can exert antitumor effects by activating immune reaction, providing more evidence for the development of GZSP-based functional foods and anticancer drugs serving as human colon cancer prevention. PRACTICAL APPLICATIONS: Natural products from medicinal and edible plant are great sources of phytochemicals beneficial to human health, such as tea polyphenols, carotenoids, and phytosterols, etc. In this study, GZSP, the polysaccharides from a well-received fruit, Ziziphus jujube cv. Goutouzao, has been comprehensively investigated. The results show that GZSP fights against free radicals commonly found in human circulation, a property that enables it to be used as an antioxidant food additive with jujube flavor. More importantly, GZSP impedes neoplastic progression by activating immune response, as evidenced by the inhibition of colorectal carcinoma (LoVo) cells. Comparing with chemotherapies usually imposing cytotoxicity on normal tissues, natural product GZSP is able to exert the antiproliferative effects on carcinoma cells with minimal side-effects. Therefore, GZSP-based functional foods and anticancer drugs with the purpose of preventing human colon cancer formation are promising to be developed.

14.
Anal Methods ; 12(21): 2727-2734, 2020 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-32930304

RESUMO

A hybrid silica monolith containing vinyl groups was synthesized by a sol-gel method, and then ground and treated, yielding silica particles with a 3-5 µm particle size and a 10-20 nm pore size. Cellulose derivatives containing 3,5-dimethylphenylcarbamate groups and methacrylate groups regioselectively were then immobilized onto the surface of the above particles by the thiol-ene click reaction using an alkanedithiol as the crosslinking agent, thus forming a solvent-resisting crosslinked network structure attached onto the surface of the particles. The immobilization degree was more than 80%, and the back pressure of the chiral stationary phase (CSP) packed column was relatively low and was maintained at around 3.0 MPa. The as-prepared CSPs were shown to be able to effectively separate various enantiomers with different mobile phases.

15.
J Inflamm (Lond) ; 17: 30, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32874136

RESUMO

Background: Traumatic coagulopathy (TC) arises primarily from coagulation system failure to maintain adequate hemostasis after serious blood loss or trauma. Circulatory homeostasis restoration is the mainstay of the therapeutic approach to TC, but the effects are significantly inhibited by coagulopathy. Objective: To identify the therapeutic effects and underlying mechanism of compound amino acid (CAA) combined with high-dosage of vitamin B6 (VB6) on TC. Methods: Rabbit traumatic model and cellular model were used to evaluate the effect of CAA combined with high-dosage of VB6 in TC. Blood concentrations of AST and ALT were measured using the Vitros 250 device while blood APTT, PT and TT concentrations were measured using commercial diagnostics kits. Furthermore, qRT-PCR, ELISA and Western blotting were used to determine the expression of clotting factor (II, VII, IX, X and XI), inflammatory factors (TNF-α, IL-6 and IL-1ß) and HMGB1/TLR4/NF-κB signaling-related proteins, respectively. Results: In the rabbit traumatic model, CAA combined with high-dosage of VB6 therapy inhibited the high expression of AST and ALT, but increased the expression of coagulation factors. Additionally, in both the rabbit trauma model and cellular injury model, CAA combined with high-dosage of VB6 inhibited the expression of inflammatory factors (IL-6, TNF-α and IL-1ß) and proteins (HMGB1, TLR4 and p-p65) in HMGB1/TLR4/NF-κB pathway. Most importantly, over-expression of HMGB1 reversed the effect of CAA and VB6 in HUVECs and EA.hy926 cells injury model. Conclusion: CAA combined with high-dosage of VB6 alleviated TC and inhibited the expression and secretion of inflammatory factors by inhibiting HMGB1-mediated TLR4/NF-κB pathway.

16.
Viruses ; 12(9)2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32867233

RESUMO

The plant genome can produce long non-coding RNAs (lncRNAs), some of which have been identified as important regulators of gene expression. To better understand the response mechanism of rice plants to Rice black-streaked dwarf virus (RBSDV) infection, we performed a comparative transcriptome analysis between the RBSDV-infected and non-infected rice plants. A total of 1342 mRNAs and 22 lncRNAs were identified to be differentially expressed after RBSDV infection. Most differentially expressed transcripts involved in the plant-pathogen interaction pathway were upregulated after RBSDV infection, indicating the activation of rice defense response by RBSDV. A network of differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs) was then constructed. In this network, there are 56 plant-pathogen interaction-related DEmRNAs co-expressing with 20 DElncRNAs, suggesting these DElncRNAs and DEmRNAs may play essential roles in rice innate immunity against RBSDV. Moreover, some of the lncRNA-mRNA regulatory relationships were experimentally verified in rice calli by a quick and effective method established in this study. Three DElncRNAs were selected to be tested, and the results indicated that five mRNAs were found to be regulated by them. Together, we give a whole landscape of rice mRNAs and lncRNAs in response to RBSDV infection, and a feasible method to rapidly verify the lncRNA-mRNA regulatory relationship in rice.

17.
Lab Chip ; 20(17): 3120-3131, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32756693

RESUMO

Circumferential alignment of vascular smooth muscle cells (vSMCs) is critical to form an in vivo-like vascular smooth muscle layer in vitro. Although many techniques to elicit such an alignment on 3D substrates have been demonstrated, it remains a challenge to recapitulate the circumferential cellular alignment of vascular smooth muscle tissues in 3D hydrogels. Here, we propose a spring-like gelatin methacrylate (GelMA) structure formed by semi-automated reeling of a core-shell microfiber at the micro-scale. The resulting structures facilitate circumferential alignment and self-organization of encapsulated human mesenchymal stem cells (MSCs) into multilayer spring-like cellular structures. Based on the permeable tubular lumens of these structures, a perfusion culture micro-system is developed to further facilitate the vSMC differentiation of MSCs under the effect of TGF-ß1. We also evaluated the MSC contraction-induced shrinkage of the resulting cellular structures. These results demonstrate the successful in vitro regeneration of vascular smooth muscle (vSM)-like tissues in 3D environments. Compared with the substrate surface, the porous structure in hydrogels is more similar to cell microenvironments in vivo. Thus, this approach may be used to develop an in vitro model for the study of vascular tissue regeneration and the mechanism of vascular remolding during hypertension.

18.
Nat Cell Biol ; 22(9): 1056-1063, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32807901

RESUMO

p53 is the most intensively studied tumour suppressor1. The regulation of p53 homeostasis is essential for its tumour-suppressive function2,3. Although p53 is regulated by an array of post-translational modifications, both during normal homeostasis and in stress-induced responses2-4, how p53 maintains its homeostasis remains unclear. UFMylation is a recently identified ubiquitin-like modification with essential biological functions5-7. Deficiency in this modification leads to embryonic lethality in mice and disease in humans8-12. Here, we report that p53 can be covalently modified by UFM1 and that this modification stabilizes p53 by antagonizing its ubiquitination and proteasome degradation. Mechanistically, UFL1, the UFM1 ligase6, competes with MDM2 to bind to p53 for its stabilization. Depletion of UFL1 or DDRGK1, the critical regulator of UFMylation6,13, decreases p53 stability and in turn promotes cell growth and tumour formation in vivo. Clinically, UFL1 and DDRGK1 expression are downregulated and positively correlated with levels of p53 in a high percentage of renal cell carcinomas. Our results identify UFMylation as a crucial post-translational modification for maintenance of p53 stability and tumour-suppressive function, and point to UFMylation as a promising therapeutic target in cancer.


Assuntos
Proteína Supressora de Tumor p53/metabolismo , Ubiquitinação/fisiologia , Carcinoma de Células Renais/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Neoplasias Renais/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo
19.
Front Comput Neurosci ; 14: 51, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32714173

RESUMO

Sequence learning is a fundamental cognitive function of the brain. However, the ways in which sequential information is represented and memorized are not dealt with satisfactorily by existing models. To overcome this deficiency, this paper introduces a spiking neural network based on psychological and neurobiological findings at multiple scales. Compared with existing methods, our model has four novel features: (1) It contains several collaborative subnetworks similar to those in brain regions with different cognitive functions. The individual building blocks of the simulated areas are neural functional minicolumns composed of biologically plausible neurons. Both excitatory and inhibitory connections between neurons are modulated dynamically using a spike-timing-dependent plasticity learning rule. (2) Inspired by the mechanisms of the brain's cortical-striatal loop, a dependent timing module is constructed to encode temporal information, which is essential in sequence learning but has not been processed well by traditional algorithms. (3) Goal-based and episodic retrievals can be achieved at different time scales. (4) Musical memory is used as an application to validate the model. Experiments show that the model can store a huge amount of data on melodies and recall them with high accuracy. In addition, it can remember the entirety of a melody given only an episode or the melody played at different paces.

20.
Dent Mater ; 36(10): 1289-1302, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32651018

RESUMO

OBJECTIVES: To investigate the influence of surface microstructure and chemistry after modification on surface bioactivity and biosafety of carbon fibers reinforced PEEK (CF/PEEK) composites as implants. METHODS: CF/PEEK composites with different CF contents (0 wt%, 25 wt% and 40 wt%) were prepared by injection molding and treated by concentrated sulfuric acid. A porous network was produced on the surface by etching action. Subsequently, the sulfonated CF/PEEK composites were immersed in GO solution. Thus, GO wrinkles with abundant functional groups were wrapped outside the porous nanostructures on CF/PEEK composites. The cell responses in vitro (proliferation, alkaline phosphatase activity and cell mineralization), osseointegration in vivo (fluorochrome labeling, H&E staining and X-ray analysis) and biosafety were investigated. RESULTS: The pore size of porous layer on the surface of CF/PEEK composites was improved with the increase of CF content. Subsequently, a silk-like GO wrinkles on the surface were formed by GO modification. And the more CF content, the greater the degree of GO wrinkles. The results revealed that GO functional wrinkle up-regulated surface hydrophilicity. In vitro cell experiments showed that porous nanostructures and GO wrinkles dramatically promoted initial cell behaviors. Significantly, GO modified composites exhibited enhanced bioactivity and osseointegration in vivo. Fortunately, the GO wrapped porous CF/PEEK composites displayed biosafety. SIGNIFICANCE: The surface modification is effective and the modified composites showed great bioactivity. The GO wrapped porous CF/PEEK composites would hold great potential for implants.

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