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1.
J Nanosci Nanotechnol ; 20(5): 3246-3251, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31635671

RESUMO

Developing new advanced nonenzymatic electrochemical nano-sensors for glucose detection has attracted intensive attraction. In this work, we designed a novel nanocomposite nonenzymatic glucose sensor by fabricating hierarchically nanostructured metal nickel on titania nanowire arrays, which was loaded on a transparent conductive substrate (i.e., fluorine-doped tin oxide, FTO) surface by mild hydrothermal method. Due to the large surface area of the hierarchically nanostructured Ni and fast electron transfer of the TiO2 nanowire arrays electrode, the nanocomposite electrode shows excellent electrochemical activity toward the oxidation of glucose. The electrode exhibits high sensitivity in detecting glucose concentration (1472 µA mM-1 cm-2) with a wide linear range from 2×10-4 M to 2×10-3 M, fast response time (within 5 s), and small detection limit (10 µM) (S/N = 3). The good analytical performance, low cost and simple preparation method make this novel electrode material promising for the development of effective glucose nonenzymatic glucose sensor.

2.
Mol Cancer ; 18(1): 163, 2019 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-31735169

RESUMO

BACKGROUND: Dynamic N6-methyladenosine (m6A) modification was previously identified as a ubiquitous post-transcriptional regulation that affected mRNA homeostasis. However, the m6A-related epitranscriptomic alterations and functions remain elusive in human cancer. Here we aim to identify the profile and outcome of m6A-methylation in hepatocellular carcinoma (HCC). RESULTS: Using liquid chromatography-tandem mass spectrometry and m6A-immunoprecipitation in combination with high-throughput sequencing, we determined the m6A-mRNA levels in human HCC. Human HCC exhibited a characteristic gain of m6A modification in tandem with an increase of mRNA expression, owing to YTH domain family 2 (YTHDF2) reduction. The latter predicted poor classification and prognosis of HCC patients, and highly correlated with HCC m6A landscape. YTHDF2 silenced in human HCC cells or ablated in mouse hepatocytes provoked inflammation, vascular reconstruction and metastatic progression. Mechanistically, YTHDF2 processed the decay of m6A-containing interleukin 11 (IL11) and serpin family E member 2 (SERPINE2) mRNAs, which were responsible for the inflammation-mediated malignancy and disruption of vascular normalization. Reciprocally, YTHDF2 transcription succumbed to hypoxia-inducible factor-2α (HIF-2α). Administration of a HIF-2α antagonist (PT2385) restored YTHDF2-programed epigenetic machinery and repressed liver cancer. CONCLUSION: Our results have characterized the m6A-mRNA landscape in human HCC and revealed YTHDF2 as a molecular 'rheostat' in epitranscriptome and cancer progression.

3.
J Biol Chem ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31753916

RESUMO

N 6-methyladenosine (m6A) is the most abundant post-transcriptional mRNA modification in eukaryotes and exerts many of its effects on gene expression through reader proteins that bind specifically to m6A-containing transcripts. Fragile X mental retardation protein (FMRP), an RNA-binding protein, has previously been shown to affect the translation of target mRNAs and trafficking of mRNA granules. Loss of function of FMRP causes fragile X syndrome, the most common form of inherited intellectual disability in humans. Using HEK293T cells, siRNA-mediated gene knockdown, cytoplasmic and nuclear fractions, and RNA-seq and LC-MS/MS analyses, we demonstrate here that FMRP binds directly to a collection of m6A sites on mRNAs. FMRP depletion increased mRNA m6A levels in the nucleus. Moreover, the abundance of FMRP targets in the cytoplasm relative to the nucleus was decreased in Fmr1-KO mice, an effect also observed in highly methylated genes. We conclude that FMRP may affect the nuclear export of m6A-modified RNA targets.

4.
Medicine (Baltimore) ; 98(45): e17288, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702608

RESUMO

BACKGROUND: Microsurgery is a treatment option for dural arteriovenous fistula (DAF), but its efficacy is still unclear. This study aims to assess the efficacy and safety of microsurgery for the treatment of patients with DAF. METHODS: We will carry out this study assessing the use of microsurgery in patients with DAF from the following electronic databases: PUBMED, EMBASE, Cochrane Library, CINAHL, PsycINFO, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. All those databases will be searched from inception to the present without language limitations. Two independent authors will perform study selection, data extraction, and methodological quality assessment. RevMan 5.3 Software will be applied for statistical analysis. RESULTS: This study will assess the efficacy and safety of microsurgery for the treatment of patients with DAF through measuring initial treatment failure, late recurrence, neurological improvement, quality of life, and complications. CONCLUSION: This study will provide most recent evidence of microsurgery for the treatment of patients with DAF. DISSEMINATION AND ETHICS: The findings of this systematic review will be published in peer-reviewed journals. This systematic review dose not needs ethic approval, because it just analyzes the published data without individual information involvement. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019144851.


Assuntos
Malformações Vasculares do Sistema Nervoso Central/cirurgia , Microcirurgia/métodos , Humanos , Microcirurgia/efeitos adversos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Projetos de Pesquisa , Falha de Tratamento , Resultado do Tratamento
5.
Clin Chem ; 65(11): 1414-1425, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31575611

RESUMO

BACKGROUND: Long-term complications of type 2 diabetes (T2D), such as macrovascular and microvascular events, are the major causes for T2D-related disability and mortality. A clinically convenient, noninvasive approach for monitoring the development of these complications would improve the overall life quality of patients with T2D and help reduce healthcare burden through preventive interventions. METHODS: A selective chemical labeling strategy for 5-hydroxymethylcytosines (5hmC-Seal) was used to profile genome-wide 5hmCs, an emerging class of epigenetic markers implicated in complex diseases including diabetes, in circulating cell-free DNA (cfDNA) from a collection of Chinese patients (n = 62). Differentially modified 5hmC markers between patients with T2D with and without macrovascular/microvascular complications were analyzed under a case-control design. RESULTS: Statistically significant changes in 5hmC markers were associated with T2D-related macrovascular/microvascular complications, involving genes and pathways relevant to vascular biology and diabetes, including insulin resistance and inflammation. A 16-gene 5hmC marker panel accurately distinguished patients with vascular complications from those without [testing set: area under the curve (AUC) = 0.85; 95% CI, 0.73-0.96], outperforming conventional clinical variables such as urinary albumin. In addition, a separate 13-gene 5hmC marker panel could distinguish patients with single complications from those with multiple complications (testing set: AUC = 0.84; 95% CI, 0.68-0.99), showing superiority over conventional clinical variables. CONCLUSIONS: The 5hmC markers in cfDNA reflected the epigenetic changes in patients with T2D who developed macrovascular/microvascular complications. The 5hmC-Seal assay has the potential to be a clinically convenient, noninvasive approach that can be applied in the clinic to monitor the presence and severity of diabetic vascular complications.

6.
Blood Adv ; 3(19): 2790-2799, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31570490

RESUMO

An elevated level of circulating cell-free DNA (cfDNA) has been associated with tumor bulk and poor prognosis in diffuse large B-cell lymphoma (DLBCL), but the tumor-specific molecular alterations in cfDNA with prognostic significance remain unclear. We investigated the association between 5-hydroxymethylcytosines (5hmC), a mark of active demethylation and gene activation, in cfDNA from blood plasma and prognosis in newly diagnosed DLBCL patients. We used 5hmC-Seal, a highly sensitive chemical labeling technique, to profile genome-wide 5hmC in plasma cfDNA from 48 DLBCL patients at the University of Chicago Medical Center between 2010 and 2013. Patients were followed through 31 December 2017. We found a distinct genomic distribution of 5hmC in cfDNA marking tissue-specific enhancers, consistent with their putative roles in gene regulation. The 5hmC profiles in cfDNA differed by cell of origin and were associated with clinical prognostic factors, including stage and the International Prognostic Index. We developed a 29 gene-based weighted prognostic score (wp-score) for predicting event-free survival (EFS) and overall survival (OS) by applying the elastic net regularization on the Cox proportional-hazards model. The wp-scores outperformed (eg, prognostic accuracy, sensitivity, specificity) established prognostic factors in predicting EFS and OS. In multivariate Cox models, patients with high wp-scores had worse EFS (hazard ratio, 9.17; 95% confidence interval, 2.01-41.89; P = .004) compared with those in the low-risk group. Our findings suggest that the 5hmC signatures in cfDNA at the time of diagnosis are associated with clinical outcomes and may provide a novel minimally invasive prognostic approach for DLBCL.

7.
Nat Commun ; 10(1): 4595, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597913

RESUMO

N6-methyladenosine (m6A) is the most prevalent internal modification of mRNAs in most eukaryotes. Here we show that RNAs of human respiratory syncytial virus (RSV) are modified by m6A within discreet regions and that these modifications enhance viral replication and pathogenesis. Knockdown of m6A methyltransferases decreases RSV replication and gene expression whereas knockdown of m6A demethylases has the opposite effect. The G gene transcript contains the most m6A modifications. Recombinant RSV variants expressing G transcripts that lack particular clusters of m6A display reduced replication in A549 cells, primary well differentiated human airway epithelial cultures, and respiratory tracts of cotton rats. One of the m6A-deficient variants is highly attenuated yet retains high immunogenicity in cotton rats. Collectively, our results demonstrate that viral m6A methylation upregulates RSV replication and pathogenesis and identify viral m6A methylation as a target for rational design of live attenuated vaccine candidates for RSV and perhaps other pneumoviruses.

8.
J Periodontal Res ; 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31630411

RESUMO

BACKGROUND: Mechanical stimuli can cause periodontal tissue reconstruction. Studies have found that changes in metabolites can be the terminal effect of integrin-mediated mechanical signaling. As a key kinase in integrin regulation, integrin-linked kinase (ILK) mediates mechanical signal transduction, which may contribute to metabolite changes. Defining the components of small-molecule metabolites can optimize mechanical stimuli and periodontal tissue reconstruction. Our purpose is to detect the effect of ILK-mediated mechanical signaling on intracellular small-molecule metabolites (amino acids and organic acids) in human periodontal ligament fibroblasts (HPDLFs). METHODS: Primary HPDLFs were isolated by enzyme digestion method. Tensile stresses were applied on HPDLFs in vitro using a Flexcell system. ILK gene in HPDLFs was knocked down by RNA interference (RNAi). Twenty common amino acids and seven organic acids in HPDLFs were analyzed by gas chromatography/mass spectrometry technique. RESULTS: Five amino acids (ie, alanine, glutamine, glutamate, glycine, and threonine) and three organic acids (ie, pyruvate, lactate, and citric acid) were found to be changed remarkably after mechanical stretching. In addition, baseline levels of four amino acids (ie, glutamate, glutamine, threonine, and glycine) and two organic acids (ie, lactate and citric acid) were significantly different in ILK knockdown compared with wild-type HPDLFs. CONCLUSION: This study suggests that five amino acids (ie, alanine, glutamine, glutamate, glycine, and threonine) and three organic acids (ie, pyruvate, lactate, and citric acid) may act as cellular mediators for mechanical signals in HPDLFs. Among them, four amino acids (ie, glutamate, glutamine, threonine, and glycine) and two organic acids (ie, lactate and citric acid) may be closely linked to ILK.

9.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 33(10): 1310-1319, 2019 Oct 15.
Artigo em Chinês | MEDLINE | ID: mdl-31544445

RESUMO

Objective: To investigate the heterotopic osteogenesis of tissue engineered bone using the co-culture system of vascular endothelial cells (VECs) and adipose-derived stem cells (ADSCs) as seed cells. Methods: The partially deproteinized biological bone (PDPBB) was prepared by fibronectin combined with partially deproteinized bone (PDPB). The ADSCs of 18-week-old Sprague Dawley (SD) rats and VECs of cord blood of full-term pregnant SD rats were isolated and cultured. Three kinds of tissue engineered bone were constructed in vitro: PDPBB+VECs (group A), PDPBB+ADSCs (group B), PDPBB+co-cultured cells (VECs∶ADSCs was 1∶1, group C), and PDPBB was used as control group (group D). Scanning electron microscopy was performed at 10 days after cell transplantation to observe cell adhesion on scaffolds. Forty-eight 18-week-old SD rats were randomly divided into groups A, B, C, and D, with 12 rats in each group. Four kinds of scaffolds, A, B, C, and D, were implanted into the femoral muscle bags of rats in corresponding groups. The animals were killed at 2, 4, 8, and 12 weeks after operation for gross observation, HE staining and Masson staining histological observation, and the amount of bone collagen was measured quantitatively by Masson staining section. Results: Scanning electron microscopy showed that the pores were interconnected in PDPB materials, and a large number of lamellar protein crystals on the surface of PDPBB modified by fibronection were loosely attached to the surface of the scaffold. After 10 days of co-culture PDPBB and cells, a large number of cells attached to PDPBB and piled up with each other to form cell clusters in group C. Polygonal cells and spindle cells were mixed and distributed, and some cells grew along bone trabeculae to form cell layers. Gross observation showed that the granulation tissue began to grow into the material pore at 2 weeks after operation. In group C, a large number of white cartilage-like substances were gradually produced on the surface of the material after 4 weeks, and the surface of the material was uneven. At 12 weeks, the amount of blood vessels on the surface of group A increased, and the material showed consolidation; there was a little white cartilage-like material on the surface of group B, but the pore size of the material did not decrease significantly; in group D, the pore size of the material did not decrease significantly. Histological observation showed that there was no significant difference in the amount of bone collagen between groups at 2 weeks after operation ( F=2.551, P=0.088); at 4, 8, and 12 weeks after operation, the amount of bone collagen in group C was significantly higher than that in other 3 groups, and that in group B was higher than that in group D ( P<0.05); there was no significant difference between group A and groups B, D ( P>0.05). Conclusion: The ability of heterotopic osteogenesis of tissue engineered bone constructed by co-culture VECs and ADSCs was the strongest.


Assuntos
Células Endoteliais , Osteogênese , Animais , Células Cultivadas , Técnicas de Cocultura , Células-Tronco Mesenquimais , Ratos , Ratos Sprague-Dawley , Células-Tronco , Engenharia Tecidual , Tecidos Suporte
10.
Nat Methods ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31548705

RESUMO

Chemical modifications to messenger RNA are increasingly recognized as a critical regulatory layer in the flow of genetic information, but quantitative tools to monitor RNA modifications in a whole-transcriptome and site-specific manner are lacking. Here we describe a versatile platform for directed evolution that rapidly selects for reverse transcriptases that install mutations at sites of a given type of RNA modification during reverse transcription, allowing for site-specific identification of the modification. To develop and validate the platform, we evolved the HIV-1 reverse transcriptase against N1-methyladenosine (m1A). Iterative rounds of selection yielded reverse transcriptases with both robust read-through and high mutation rates at m1A sites. The optimal evolved reverse transcriptase enabled detection of well-characterized m1A sites and revealed hundreds of m1A sites in human mRNA. This work develops and validates the reverse transcriptase evolution platform, and provides new tools, analysis methods and datasets to study m1A biology.

11.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 857-861, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31515775

RESUMO

OBJECTIVE: To carry out mutation analysis for patients with myelodysplastic syndromes (MDS) and a normal karyotype. METHODS: Targeted capture and next-generation sequencing (NGS) was carried out using a customized 49-gene panel. FLT3 internal tandem duplication (FLT3-ITD), CALR, NPM1 and CEBPA mutations were detected by PCR and Sanger sequencing. RESULTS: Sixty-two patients (80.5%) were found to harbor at least one mutation. Each patient has carried 2.21 mutations in average. Coexistence of ≥ 3 mutations was common (43.7%). The most commonly mutated genes were RUNX1 (23.4%, 18/77), ASXL1 (18.2%, 14/77), NPM1 (15.6%, 12/77), U2AF1 (15.6%, 12/77), DNMT3A (11.7%, 9/77). Patients with SF3B1 mutations were significantly older than those with ASXL1 mutations (P=0.023). Mutations of the DNMT3A gene were significantly associated with the blood platelet level compared with BCOR mutations (P=0.02). No significant difference was found in the number and rate of mutations between those under or above 60-year-old. Among 67 patients with clinical follow-up, 20 (29.8%) has transformed to acute myeloid leukemia, and the time of transformation has ranged from 1 to 44 months, with a average of 5.3 months. RUNX1, U2AF1 and FLT3 mutations are associated with leukemic transformation. CONCLUSION: Coexistence of ≥ 3 mutations are frequent among patients with normal-karyotype MDS. Certain mutations are associated with age and leukemic transformation.


Assuntos
Análise Mutacional de DNA , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Fatores Etários , Humanos , Cariótipo , Pessoa de Meia-Idade , Mutação , Prognóstico
12.
Cancer Lett ; 467: 58-71, 2019 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-31560934

RESUMO

Chromatinolysis refers to enzymatic degradation of nuclear DNA and is regarded as one of the crucial events leading to cell death. Mixed-lineage kinase domain-like protein (MLKL) has been identified as a key executor of necroptosis, but it remains unclear whether MLKL contributes to necroptosis via regulation of chromatinolysis. In this study, we find that shikonin induces MLKL activation and chromatinolysis in glioma cells in vitro and in vivo, which are accompanied with nuclear translocation of AIF and γ-H2AX formation. In vitro studies reveal that inhibition of MLKL with its specific inhibitor NSA or knockdown of MLKL with siRNA abrogates shikonin-induced glioma cell necroptosis, as well as chromatinolysis. Mechanistically, activated MLKL targets mitochondria and triggers excessive generation of mitochondrial superoxide, which promotes AIF translocation into nucleus via causing mitochondrial depolarization and aggravates γ-H2AX formation via improving intracellular accumulation of ROS. Inhibition of nuclear level of AIF by knockdown of AIF with siRNA or mitigation of γ-H2AX formation by suppressing ROS with antioxidant NAC effectively prevents shikonin-induced chromatinolysis. Then, we found that RIP3 accounts for shikonin-induced activation of MLKL, and activated MLKL reversely up-regulates the protein level of CYLD and promotes the activation of RIP1 and RIP3. Taken together, our data suggest that MLKL contributes to shikonin-induced glioma cell necroptosis via promotion of chromatinolysis, and shikonin induces a positive feedback between MLKL and its upstream signals RIP1 and RIP3.

13.
Neurosurgery ; 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31555814

RESUMO

BACKGROUND: No prior reports have focused on the natural history and long-term outcomes of intramedullary spinal cord cavernous malformations (ISCCMs) in children. OBJECTIVE: To investigate the clinical characteristics and long-term outcomes of pediatric ISCCMs and identify the risk of hemorrhage. METHODS: We retrospectively reviewed a series of 20 pediatric patients (<18 yr old) from a consecutive series of 254 patients with ISCCMs evaluated at a single institution. RESULTS: Of the 20 pediatric patients, 9 (45.0%) presented with a severe neurological and disability status. The annual hemorrhagic rate in pediatric patients was 8.2%/patient/year. After initial overt hemorrhage events, the annual overt rehemorrhage rate increased to 30.7%/patient/year. In 234 adult patients, the respective rates were 2.8% and 7.4%. Thoracic or lumbar level lesions (P = .002, OR = 3.425, 95% CI = 1.588-7.387) and rehemorrhagic events (P = .005, OR = 3.209, 95% CI = 1.415-7.279) were more likely to follow an aggressive course. There were no significant differences in the sex distribution, location and size of lesions, types of symptoms, likelihood of a severe neurological and disability status, or immediate and long-term postoperative outcomes between pediatric and adult patients with ISCCMs. CONCLUSION: The annual overt hemorrhage rate and rehemorrhage rate of ISCCMs were higher in affected children than in affected adults. Surgical resection of pediatric ISCCMs remains the preferred therapeutic option and provides favorable outcomes.

14.
World Neurosurg ; 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31520758

RESUMO

BACKGROUND: Compared with intracranial aneurysms (IAs) at other locations, pericallosal artery aneurysms (PAAs) have demonstrated an extremely high risk of rupture. However, owing to their rarity, our understanding of their morphological characteristics has been limited, and whether the morphological characteristics of PAAs contribute to this high rupture risk has remained unexplored. In the present study, we aimed to provide a detailed description of the morphological characteristics of PAAs and investigate the association between its morphology and rupture risk compared with anterior circulation IAs at other locations. METHODS: A total of 40 patients with 45 PAAs and 348 patients with 392 anterior circulation IAs at other locations were recruited. The clinical and radiological data for these patients were retrospectively reviewed. The differences in the morphological parameters, including the aneurysm diameter, neck width, height, width, parent artery diameter, inflow angle, aspect ratio (AR), size ratio (SR), and aneurysm diameter/width ratio, between PAAs and other IA groups were compared. RESULTS: Of the 45 PAAs, 22 (48.9%) had ruptured. The proportion of ruptured aneurysms was greater for PAAs than for anterior circulation IAs at other locations. For both ruptured and unruptured anterior circulation IAs, PAAs had the highest AR and SR among all IA groups and had the largest inflow angle. CONCLUSION: The morphological characteristics of PAAs are unique. Compared with other anterior circulation IAs, PAAs have significantly increased ARs, SRs, and inflow angles, which, ultimately, promote their high propensity toward rupture.

15.
Mol Cell ; 76(1): 70-81.e9, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31445886

RESUMO

N6-methyladenosine (m6A) modification occurs co-transcriptionally and impacts pre-mRNA processing; however, the mechanism of co-transcriptional m6A-dependent alternative splicing regulation is still poorly understood. Heterogeneous nuclear ribonucleoprotein G (hnRNPG) is an m6A reader protein that binds RNA through RRM and Arg-Gly-Gly (RGG) motifs. Here, we show that hnRNPG directly binds to the phosphorylated carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII) using RGG motifs in its low-complexity region. Through interactions with the phosphorylated CTD and nascent RNA, hnRNPG associates co-transcriptionally with RNAPII and regulates alternative splicing transcriptome-wide. m6A near splice sites in nascent pre-mRNA modulates hnRNPG binding, which influences RNAPII occupancy patterns and promotes exon inclusion. Our results reveal an integrated mechanism of co-transcriptional m6A-mediated splicing regulation, in which an m6A reader protein uses RGG motifs to co-transcriptionally interact with both RNAPII and m6A-modified nascent pre-mRNA to modulate RNAPII occupancy and alternative splicing.

17.
Nat Commun ; 10(1): 3399, 2019 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363082

RESUMO

Identifying driver genes from somatic mutations is a central problem in cancer biology. Existing methods, however, either lack explicit statistical models, or use models based on simplistic assumptions. Here, we present driverMAPS (Model-based Analysis of Positive Selection), a model-based approach to driver gene identification. This method explicitly models positive selection at the single-base level, as well as highly heterogeneous background mutational processes. In particular, the selection model captures elevated mutation rates in functionally important sites using multiple external annotations, and spatial clustering of mutations. Simulations under realistic evolutionary models demonstrate the increased power of driverMAPS over current approaches. Applying driverMAPS to TCGA data of 20 tumor types, we identified 159 new potential driver genes, including the mRNA methyltransferase METTL3-METTL14. We experimentally validated METTL3 as a tumor suppressor gene in bladder cancer, providing support to the important role mRNA modification plays in tumorigenesis.

18.
Biochem Biophys Res Commun ; 518(3): 590-597, 2019 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-31445705

RESUMO

RSL3 is a type of small molecular compound which can inactivate glutathione peroxidase 4 (GPX4) and induce ferroptosis, but its role in glioma cell death remains unclear. In this study, we found RSL3 inhibited the viabilities of glioma cells and induced glioma cell death in a dose-dependent manner. In vitro studies revealed that RSL3-induced cell death was accompanied with the changes of autophagy-associated protein levels and was alleviated by pretreatment of 3-Methyladenine, bafilomycin A1 and knockdown of ATG5 with siRNA. The ATP and pyruvate content as well as the protein levels of HKII, PFKP, PKM2 were decreased in cells treated by RSL3, indicating that RSL3 induced glycolysis dysfunction in glioma cells. Moreover, supplement of exterior sodium pyruvate, which was a final product of glycolysis, not only inhibited the changes of autophagy-associated protein levels caused by RSL3, but also prevented RSL3-induced cell death. In vivo data suggested that the inhibitory effect of RSL3 on the growth of glioma cells was associated with glycolysis dysfunction and autophagy activation. Taken together, RSL3 induced autophagic cell death in glioma cells via causing glycolysis dysfunction.

19.
Sci Adv ; 5(7): eaax0250, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31281898

RESUMO

N 6-methyladenosine (m6A) is one of the most abundant messenger RNA modifications in eukaryotes involved in various pivotal processes of RNA metabolism. The most popular high-throughput m6A identification method depends on the anti-m6A antibody but suffers from poor reproducibility and limited resolution. Exact location information is of great value for understanding the dynamics, machinery, and functions of m6A. Here, we developed a precise and high-throughput antibody-independent m6A identification method based on the m6A-sensitive RNA endoribonuclease recognizing ACA motif (m6A-sensitive RNA-Endoribonuclease-Facilitated sequencing or m6A-REF-seq). Whole-transcriptomic, single-base m6A maps generated by m6A-REF-seq quantitatively displayed an explicit distribution pattern with enrichment near stop codons. We used independent methods to validate methylation status and abundance of individual m6A sites, confirming the high reliability and accuracy of m6A-REF-seq. We applied this method on five tissues from human, mouse, and rat, showing that m6A sites are conserved with single-nucleotide specificity and tend to cluster among species.

20.
J Orthop Surg Res ; 14(1): 231, 2019 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-31331380

RESUMO

BACKGROUND: This study aimed to investigate the effects of stromal cell-derived factor-1 (SDF-1) on biphasic ceramic-like biologic bone (BCBB) in vivo on the repair of large segment bone defect in rabbits. METHODS: A large-segment radius defect model of the rabbits was constructed. In the experimental group, BCBB with SDF-1 sustained-release system were implanted into the bone defect site. Other three groups including normal control, autologous bone graft, and BCBB implantation without SDF-1 were set. After surgery, general observation, X-ray radiography and scoring, and tissue section staining were performed at 2, 4, 8, 12, and 24 weeks post-implantation. RESULTS: By general observation, X-ray radiography and grading and tissue section staining observation, we found that the BCBB carrying SDF-1 was better than those in the group of BCBB without SDF-1 (P < 0.05). BCBB scaffold had certain bone conduction capacity, and the BCBB scaffold carrying SDF-1 had improved bone conduction ability and possessed bone induction ability. In the case of carrying SDF-1, it can be used to repair large bone defects in a shorter time than simply using BCBB, which is equivalent to the effect of autologous bone. CONCLUSION: BCBB scaffold carrying SDF-1 can promote the repair effect on a large bone defect, which is equivalent to the effect of autologous bone.

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