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1.
MBio ; 10(4)2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363026

RESUMO

Endogenous retroviruses (ERVs) are transposable elements that cause host genome instability and usually play deleterious roles in disease such as tumorigenesis. Recent advances also suggest that this "enemy within" may encode a viral mimic to induce antiviral immune responses through viral sensors. Here, through whole-genome transcriptome analysis with RNA sequencing (RNA-Seq), we discovered that a full-length ERV-derived long noncoding RNA (lncRNA), designated lnc-EPAV (ERV-derived lncRNA positively regulates antiviral responses), was a positive regulator of NF-κB signaling. lnc-EPAV expression was rapidly upregulated by viral RNA mimics or RNA viruses to facilitate the expression of RELA, an NF-κB subunit that plays a crucial role in antiviral responses. Transcriptome analysis of lnc-EPAV-silenced macrophages showed that lnc-EPAV was critical for RELA target gene expression and innate immune responses. Consistently, lnc-EPAV-deficient mice exhibited reduced expression of type I interferons (IFNs) and, consequently, increased viral loads and mortality following lethal RNA virus infection. Mechanistically, lnc-EPAV promoted expression of RELA by competitively binding to and displacing SFPQ, a transcriptional repressor of Rela Altogether, our work demonstrates an alternative mechanism by which ERVs regulate antiviral immune responses.IMPORTANCE Endogenous retroviruses are transposable genetic elements comprising 8% to 10% of the human and mouse genomes. Although most ERVs have been inactivated due to deleterious mutations, some are still transcribed. However, the biological functions of transcribed ERVs are largely unknown. Here, we identified a full-length ERV-derived lncRNA, designated lnc-EPAV, as a positive regulator of host innate immune responses. We found that silencing lnc-EPAV impaired virus-induced cytokine production, resulting in increased viral replication in cells. The lnc-EPAV-deficient mice exhibited enhanced susceptibility to viral challenge. We also found that lnc-EPAV regulated expression of RELA, an NF-κB subunit that plays a critical role in antiviral responses. ERV-derived lncRNA coordinated with a transcription repressor, SFPQ, to control Rela transcription. Our report provides new insights into the previously unrecognized immune gene regulatory mechanism of ERV-derived lncRNAs.

2.
Aging (Albany NY) ; 11(13): 4407-4437, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31257225

RESUMO

Cellular senescence has been regarded as a mechanism of tumor suppression. Studying the regulation of gene expression at various levels in cell senescence will shed light on cancer therapy. Alternative polyadenylation (APA) regulates gene expression by altering 3' untranslated regions (3' UTR) and plays important roles in diverse biological processes. However, whether APA of a specific gene functions in both cancer and senescence remains unclear. Here, we discovered that 3' UTR of HN1 (or JPT1) showed shortening in cancers and lengthening in senescence, correlated well with its high expression in cancer cells and low expression in senescent cells, respectively. HN1 transcripts with longer 3' UTR were less stable and produced less protein. Down-regulation of HN1 induced senescence-associated phenotypes in both normal and cancer cells. Patients with higher HN1 expression had lower survival rates in various carcinomas. Interestingly, down-regulating the splicing factor HNRNPA1 induced 3' UTR lengthening of HN1 and senescence-associated phenotypes, which could be partially reversed by overexpressing HN1. Together, we revealed for the first time that HNRNPA1-mediated APA of HN1 contributed to cancer- and senescence-related phenotypes. Given senescence is a cancer prevention mechanism, our discovery indicates the HNRNPA1-HN1 axis as a potential target for cancer treatment.

3.
Nat Commun ; 10(1): 3210, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324807

RESUMO

Accumulating evidence indicates that the zinc-finger transcription factor ZEB1 is predominantly expressed in the stroma of several tumours. However, the role of stromal ZEB1 in tumour progression remains unexplored. In this study, while interrogating human databases, we uncover a remarkable decrease in relapse-free survival of breast cancer patients expressing high ZEB1 levels in the stroma. Using a mouse model of breast cancer, we show that ZEB1 inactivation in stromal fibroblasts suppresses tumour initiation, progression and metastasis. We associate this with reduced extracellular matrix remodeling, immune cell infiltration and decreased angiogenesis. ZEB1 deletion in stromal fibroblasts increases acetylation, expression and recruitment of p53 to FGF2/7, VEGF and IL6 promoters, thereby reducing their production and secretion into the surrounding stroma. Importantly, p53 ablation in ZEB1 stroma-deleted mammary tumours sufficiently recovers the impaired cancer growth and progression. Our findings identify the ZEB1/p53 axis as a stroma-specific signaling pathway that promotes mammary epithelial tumours.

4.
Nucleic Acids Res ; 47(15): 7886-7900, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31216029

RESUMO

The intron-lariat spliceosome (ILS) complex is highly conserved among eukaryotes, and its disassembly marks the end of a canonical splicing cycle. In this study, we show that two conserved disassembly factors of the ILS complex, Increased Level of Polyploidy1-1D (ILP1) and NTC-Related protein 1 (NTR1), positively regulate microRNA (miRNA) biogenesis by facilitating transcriptional elongation of MIRNA (MIR) genes in Arabidopsis thaliana. ILP1 and NTR1 formed a stable complex and co-regulated alternative splicing of more than a hundred genes across the Arabidopsis genome, including some primary transcripts of miRNAs (pri-miRNAs). Intriguingly, pri-miRNAs, regardless of having introns or not, were globally down-regulated when the ILP1 or NTR1 function was compromised. ILP1 and NTR1 interacted with core miRNA processing proteins Dicer-like 1 and Serrate, and were required for proper RNA polymerase II occupancy at elongated regions of MIR chromatin, without affecting either MIR promoter activity or pri-miRNA decay. Our results provide further insights into the regulatory role of spliceosomal machineries in the biogenesis of miRNAs.

5.
BMC Med Imaging ; 19(1): 43, 2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31126251

RESUMO

BACKGROUND: The purpose was to investigate the difference of detection rate of incidental pancreatic cystic lesions (PCLs) with computed tomography (CT) and magnetic resonance imaging (MRI) and to compare the difference between CT and MRI and to explore the effect of this difference on surgical resection. METHODS: We reviewed the diagnostic reports for incidental PCLs between 2013 and 2016. Images of PCLs would be re-evaluated. Clinical and imaging data were recorded. The chi-square and independent t-test were conducted for categorical and continuous variables. RESULTS: The prevalence of PCLs was 1.91% (1038/54210) and 3.36% (1282/38099) on CT and MRI respectively, and increased with increasing age (P < 0.001). No significant differences were found in the annual prevalence of PCLs on CT (P = 0.796) and MRI (P = 0.213) from 2013 to 2016 while the number of examinations was increasing every year. The annual detection rate of MRI for small PCLs (< 20 mm) was significantly higher than CT (P < 0.001), but was not significantly different for large PCLs (≥20 mm). The rate of surgical resection of PCLs (≥20 mm) in MRI group was higher than CT (55.2% vs. 37.0%, P < 0.001). CONCLUSIONS: The detection rate of PCLs on CT and MRI tended to be stable despite increasing scan volumes. Female had a slightly more frequency of PCLs than male. MRI detected more small PCLs(< 20 mm) and had higher impact on surgical resection of large PCL(≥20 mm) compared with CT.

6.
Life Sci ; 229: 225-232, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31085244

RESUMO

AIMS: Cellular senescence is a well-known cancer prevention mechanism, inducing cancer cells to senescence can enhance cancer immunotherapy. However, how cellular senescence is regulated is not fully understood. Dynamic chromatin changes have been discovered during cellular senescence, while the causality remains elusive. BAZ1A, a gene coding the accessory subunit of ATP-dependent chromatin remodeling complex, showed decreased expression in multiple cellular senescence models. We aim to investigate the functional role of BAZ1A in regulating senescence in cancer and normal cells. MATERIALS AND METHODS: Knockdown of BAZ1A was performed via lentivirus mediated short hairpin RNA (shRNA) in various cancer cell lines (A549 and U2OS) and normal cells (HUVEC, NIH3T3 and MEF). A series of senescence-associated phenotypes were quantified by CCK-8 assay, SA-ß-Gal staining and EdU incorporation assay, etc. KEY FINDINGS: Knockdown (KD) of BAZ1A induced series of senescence-associated phenotypes in both cancer and normal cells. BAZ1A-KD caused the upregulated expression of SMAD3, which in turn activated the transcription of p21 coding gene CDKN1A and resulted in senescence-associated phenotypes in human cancer cells (A549 and U2OS). SIGNIFICANCE: Our results revealed chromatin remodeling modulator BAZ1A acting as a novel regulator of cellular senescence in both normal and cancer cells, indicating a new target for potential cancer treatment.


Assuntos
Neoplasias Ósseas/patologia , Senescência Celular , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/metabolismo , Osteossarcoma/patologia , Fatores de Transcrição/metabolismo , Células A549 , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/metabolismo , Células Cultivadas , Proteínas Cromossômicas não Histona/genética , Fibroblastos/citologia , Fibroblastos/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Células NIH 3T3 , Osteossarcoma/genética , Osteossarcoma/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética
7.
Aging (Albany NY) ; 11(5): 1356-1388, 2019 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-30835716

RESUMO

Down-regulated splicing factor SRSF3 is known to promote cellular senescence, an important biological process in preventing cancer and contributing to individual aging, via its alternative splicing dependent function in human cells. Here we discovered alternative polyadenylation (APA) dependent function of SRSF3 as a novel mechanism explaining SRSF3 downregulation induced cellular senescence. Knockdown of SRSF3 resulted in preference usage of proximal poly(A) sites and thus global shortening of 3' untranslated regions (3' UTRs) of mRNAs. SRSF3-depletion also induced senescence-related phenotypes in both human and mouse cells. These 3' UTR shortened genes were enriched in senescence-associated pathways. Shortened 3' UTRs tended to produce more proteins than the longer ones. Simulating the effects of 3' UTR shortening by overexpression of three candidate genes (PTEN, PIAS1 and DNMT3A) all led to senescence-associated phenotypes. Mechanistically, SRSF3 has higher binding density near proximal poly(A) site than distal one in 3' UTR shortened genes. Further, upregulation of PTEN by either ectopic overexpression or SRSF3-knockdown induction both led to reduced phosphorylation of AKT and ultimately senescence-associated phenotypes. We revealed for the first time that reduced SRSF3 expression could promote cellular senescence through its APA-dependent function, largely extending our mechanistic understanding in splicing factor regulated cellular senescence.

8.
Laryngoscope ; 129(9): E318-E328, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30597574

RESUMO

OBJECTIVES/HYPOTHESIS: Transformer-2 protein homolog beta (Tra2ß) generally plays an important role in various human cancers, but its role and the underlying mechanisms in laryngeal squamous cell carcinoma (LSCC) remained unknown. So this study aimed to assess the clinical significance and regulatory mechanisms of Tra2ß in LSCC. STUDY DESIGN: Laboratory analysis. METHODS: Expression of Tra2ß was compared in human LSCC tissue samples and paired adjacent normal tissue samples. The in vitro effects of Tra2ß expression in Hep-2 cells on their proliferation, invasion, and migration were assessed by CCK-8 assays, Matrigel invasion, and transwell migration assays. In addition, the effects of downregulation of Tra2ß on the activation of PI3K/AKT signaling pathway were measured using Western blot analysis. The effect of Tra2ß on the growth of tumors was detected in the Hep-2-injected xenograft models in vivo. RESULTS: Reverse-transcription quantitative polymerase chain reaction analysis and immunochemistry analysis indicated that the increased expression of Tra2ß in LSCC was significantly associated with poor differentiation, lymph node metastasis, and advanced clinical stage. In vitro knockdown of Tra2ß caused a significant decrease in the proliferation, invasion, and migration of Hep-2 cells. Tra2ß silencing decreased the expression of Bcl-2 but increased Bax and Caspase-3 both in mRNA and protein levels. Furthermore, knockdown of Tra2ß eliminated the suppressive effects of activation of PI3K/AKT signaling. In vivo knockdown of Tra2ß significantly inhibited the tumor growth of Hep-2-injected xenograft mice. CONCLUSIONS: The results of the present study demonstrated that knockdown of Tra2ß inhibits the proliferation and invasion of LSCC cells, at least partly via inhibiting PI3K/AKT signaling. LEVEL OF EVIDENCE: NA Laryngoscope, 129:E318-E328, 2019.

9.
Biochem Biophys Res Commun ; 510(1): 65-71, 2019 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-30661786

RESUMO

The encephalomyocarditis virus (EMCV) is a single-stranded RNA virus that induces sudden death, diabetes, myocarditis and nervous disorders in non-human primates. The rapid development of xenografts such as heart transplantation from pig to human raises the issue of EMCV safety in human cells. SFPQ, a proline and glutamine rich splicing factor that participates in diverse molecular functions including paraspeckle formation, microRNA synthesis and transcription regulation, is known to regulate host innate immune response to viruses. However, the role of SFPQ in EMCV infection remains unclear. Here we reported that the SFPQ was essential for EMCV replication. Depletion of SFPQ impaired EMCV production, while forced expression of SFPQ promoted viral replication. Mechanistically, loss of SFPQ affected the transcription profile of host mitochondria pathway related genes. In addition, cellular SFPQ was exploited by EMCV and accumulated in cytoplasm and it interacted with eukaryotic initiation factors and ribosomal proteins to facilitate internal ribosome entry site (IRES)-dependent translation of EMCV protein. Altogether, our work discovered host SFPQ as a new target to inhibit EMCV replication and infection.

10.
Cell Rep ; 26(4): 933-944.e4, 2019 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-30673615

RESUMO

Extracellular RNAs (exRNAs) can be released by numerous cell types in vitro, are often protected within vesicles, and can modify recipient cell function. To determine how the composition and cellular sources of exRNAs and the extracellular vesicles (EVs) that carry them change in vivo during tissue inflammation, we analyzed bronchoalveolar lavage fluid (BALF) from mice before and after lung allergen challenge. In the lung, extracellular microRNAs (ex-miRNAs) had a composition that was highly correlated with airway-lining epithelium. Using cell type-specific membrane tagging and single vesicle flow, we also found that 80% of detected vesicles were of epithelial origin. After the induction of allergic airway inflammation, miRNAs selectively expressed by immune cells, including miR-223 and miR-142a, increased and hematopoietic-cell-derived EVs also increased >2-fold. These data demonstrate that infiltrating immune cells release ex-miRNAs and EVs in inflamed tissues to alter the local extracellular environment.

11.
J Mol Cell Biol ; 11(1): 78-90, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535232

RESUMO

Stimulatory regulators for DNA methyltransferase activity, such as Dnmt3L and some Dnmt3b isoforms, affect DNA methylation patterns, thereby maintaining gene body methylation and maternal methylation imprinting, as well as the methylation landscape of pluripotent cells. Here we show that metastasis-related methyltransferase 1 (Merm1), a protein deleted in individuals with Williams-Beuren syndrome, acts as a repressive regulator of Dnmt3a. Merm1 interacts with Dnmt3a and represses its methyltransferase activity with the requirement of the binding motif for S-adenosyl-L-methionine. Functional analysis of gene regulation revealed that Merm1 is capable of maintaining hypomethylated rRNA gene bodies and co-localizes with RNA polymerase I in the nucleolus. Dnmt3a recruits Merm1, and in return, Merm1 ensures the binding of Dnmt3a to hypomethylated gene bodies. Such interplay between Dnmt3a and Merm1 facilitates transcriptional elongation by RNA polymerase I. Our findings reveal a repressive factor for Dnmt3a and uncover a molecular mechanism underlying transcriptional elongation of rRNA genes.

12.
J Immunol Res ; 2018: 6156757, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30525058

RESUMO

There are rapidly emerging efforts to explore tumor-associated macrophages (TAMs) as a tumor therapy target. Tumor cells express CD47, which can interact with the macrophages' SIRPα transmitting a "don't eat me" signal to macrophages. The expression of CD47 increases in various tumors to evade immune attack. However, the expression of CD47 in endometrial cancer (EC) and the role of CD47-SIRPα in the TAMs which mediate the progression of EC remain unclear. Our study shows that there are increased TAMs in EC which dominantly consist of M2 macrophages and contribute to the progression of EC. We confirm that CD47 is highly expressed in EC tissue using the TCGA database, qPCR, and flow cytometry. Instead of directly promoting the apoptosis of EC cells, anti-CD47 blocking antibody promoted phagocytosis of EC cells by macrophages and the increased phagocytosis ability was mediated by M2 macrophages in a coculture assay. Besides, CD47 blockade inhibited the growth of the EC tumors in vivo and increased the infiltration of macrophages with antitumor ability in the tumor microenvironment (TME). These findings might assist in developing promising strategies that blocked the CD47-SIRPa interaction for EC therapy.

13.
Am J Emerg Med ; 2018 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-30503280

RESUMO

Refractory ventricular fibrillation with cardiac arrest caused by occlusion of the left main coronary artery may rapidly become fatal. In this report, we describe the case of a 70-year-old male who presented to emergency department with chest pain. Electrocardiogram showed ST-segment elevation in leads aVR and aVL and ST-segment depression in leads v3, v4, v5, v6, 2, 3, and aVF. Occlusion of the left main coronary artery was suspected. While waiting for percutaneous coronary intervention, the patient experienced sudden refractory ventricular fibrillation with cardiac arrest. In the emergency department, resuscitation of a patient with refractory ventricular fibrillation caused by occlusion of the left main coronary artery and ongoing cardiopulmonary resuscitation is a clinical challenge. Resuscitation with extracorporeal membrane oxygenation support was initiated approximately 35 min after prolonged conventional cardiopulmonary resuscitation. Emergency coronary angiography showed almost total occlusion of the left main coronary artery. Percutaneous coronary intervention with a stent restored coronary perfusion. The patient was discharged on day 6 without serious sequelae or neurological deficits.

14.
Cell Rep ; 25(12): 3356-3370.e4, 2018 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-30566862

RESUMO

The discovery of microRNA (miRNA) sorting into extracellular vesicles (EVs) revealed a novel mode of intercellular communication and uncovered a link between cellular endomembrane compartments and small RNAs in EV-secreting cells. Using a two-step ultracentrifugation procedure to isolate EVs released by T cells, we found that 45% of tRNA fragments (tRFs), but fewer than 1% of miRNAs, were significantly enriched in EVs compared with the corresponding cellular RNA. T cell activation induced the EV-mediated release of a specific set of tRFs derived from the 5' end and 3'-internal region of tRNAs without variable loops. Inhibition of EV biogenesis pathways specifically led to the accumulation of these activation-induced EV-enriched tRFs within multivesicular bodies (MVBs). Introducing antisense oligonucleotides to inhibit these tRFs enhanced T cell activation. Taken together, these results demonstrate that T cells selectively release tRFs into EVs via MVBs and suggest that this process may remove tRFs that repress immune activation.

15.
Sci Rep ; 8(1): 17900, 2018 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-30538257

RESUMO

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.

16.
JAMA Netw Open ; 1(4)2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30294719

RESUMO

IMPORTANCE: Sex differences in genetic associations with human longevity remain largely unknown; investigations on this topic are important for individualized health care. OBJECTIVE: To explore sex differences in genetic associations with longevity. DESIGN SETTING AND PARTICIPANTS: This population-based case-control study used sex-specific genome-wide association study and polygenic risk score (PRS) analyses to examine sex differences in genetic associations with longevity. Five hundred sixty-four male and 1614 female participants older than 100 years were compared with a control group of 773 male and 1526 female individuals aged 40 to 64 years. All were Chinese Longitudinal Healthy Longevity Study participants with Han ethnicity who were recruited in 1998 and 2008 to 2014. MAIN OUTCOMES AND MEASURES: Sex-specific loci and pathways associated with longevity and PRS measures of joint effects of sex-specific loci. RESULTS: Eleven male-specific and 11 female-specific longevity loci (P < 10-5) and 35 male-specific and 25 female-specific longevity loci (10-5 ≤ P < 10-4) were identified. Each of these loci's associations with longevity were replicated in north and south regions of China in one sex but were not significant in the other sex (P = .13-.97), and loci-sex interaction effects were significant (P < .05). The associations of loci rs60210535 of the LINC00871 gene with longevity were replicated in Chinese women (P = 9.0 × 10-5) and US women (P = 4.6 × 10-5) but not significant in Chinese and US men. The associations of the loci rs2622624 of the ABCG2 gene were replicated in Chinese women (P = 6.8 × 10-5) and European women (P = .003) but not significant in both Chinese and European men. Eleven male-specific pathways (inflammation and immunity genes) and 34 female-specific pathways (tryptophan metabolism and PGC-1α induced) were significantly associated with longevity (P < .005; false discovery rate < 0.05). The PRS analyses demonstrated that sex-specific associations with longevity of the 4 exclusive groups of 11 male-specific and 11 female-specific loci (P < 10-5) and 35 male-specific and 25 female-specific loci (10-5 ≤P < 10-4) were jointly replicated across north and south discovery and target samples. Analyses using the combined data set of north and south showed that these 4 groups of sex-specific loci were jointly and significantly associated with longevity in one sex (P = 2.9 × 10-70 to 1.3 × 10-39) but not jointly significant in the other sex (P = .11 to .70), while interaction effects between PRS and sex were significant (P = 4.8 × 10-50 to 1.2 × 10-16). CONCLUSION AND RELEVANCE: The sex differences in genetic associations with longevity are remarkable, but have been overlooked by previously published genome-wide association studies on longevity. This study contributes to filling this research gap and provides a scientific basis for further investigating effects of sex-specific genetic variants and their interactions with environment on healthy aging, which may substantially contribute to more effective and targeted individualized health care for male and female elderly individuals.

17.
J Cancer Res Ther ; 14(Supplement): S644-S647, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30249881

RESUMO

Aims: Several studies suggested that diabetes mellitus (DM) was associated with the risk of glioma. However, other studies did not confirm the result. Therefore, I conducted this meta-analysis. Materials and Methods: I retrieved the PubMed, Embase, and Web of Science database, by adopting keywords "glioma," and "diabetes," "DM." The strength of the associations between DM and the risk of glioma was measured by odds ratios (ORs) with 95% confidence intervals (95% CIs). Results: Ten relevant studies were identified in the final analysis. A statistically significant association between DM and glioma risk was fond (OR = 0.84; 95% CI, 0.73-0.97; P = 0.02). In the subgroup analysis of age group, young population with DM showed decreased glioma risk (OR = 0.83; 95% CI, 0.70-0.98; P = 0.02), whereas old population with DM did not show a significant association (OR = 0.87; 95% CI, 0.65-1.16; P = 0.34). In the subgroup analysis of gender, male patients with DM showed decreased glioma risk (OR = 0.82; 95% CI, 0.68-0.99; P = 0.04), whereas female population with DM did not show a significant association (OR = 0.93; 95% CI, 0.70-1.24; P = 0.63). Conclusions: This meta-analysis suggested that DM may be associated with the reduced glioma risk.


Assuntos
Complicações do Diabetes/epidemiologia , Diabetes Mellitus/epidemiologia , Glioma/epidemiologia , Adulto , Fatores Etários , Idoso , Complicações do Diabetes/patologia , Diabetes Mellitus/patologia , Feminino , Glioma/complicações , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Proteção , Fatores de Risco , Caracteres Sexuais , Fatores Sexuais
18.
Mol Med Rep ; 18(2): 2229-2236, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29916551

RESUMO

The present study aimed to investigate the role of miR­214 on inflammation and apoptosis in the vascular system and to examine its potential mechanisms. Anti­miR­214 mimics were used to downregulate miR­214 expression in HUVECs. Cell viability and the apoptosis rate were measured using MTT assay and flow cytometry. Tumor necrosis factor (TNF)­α, interleukin (IL)­1ß, IL­6 and IL­18 levels were measured using ELISA kits. Following this, caspase­3/9, Bax, phosphatase and tensin homolog (PTEN), nuclear factor (NF)­κB and phosphorylated­(p)­protein kinase B (Akt) protein expression were analyzed using western blotting. The results demonstrated that anti­miR­214 mimics inhibited cell proliferation, increased apoptosis and inflammatory factors (TNF­α, IL­1ß, IL­6 and IL­18 levels), inhibited cell proliferation, and induced Bax protein expression in TNF­α­induced vascular endothelial cells through induction of PTEN and NF­κB protein expression and inhibition of Akt protein expression. The PTEN inhibitor inhibited the function of anti­miR­214 on apoptosis and inflammation in TNF­α­induced inflammation vascular endothelial cells through the PTEN/Akt signaling pathway. These results suggest that miR­214 mediates vascular inflammation and apoptosis via PTEN expression.


Assuntos
Apoptose , Regulação Enzimológica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , MicroRNAs/metabolismo , PTEN Fosfo-Hidrolase/biossíntese , Transdução de Sinais , Vasculite/metabolismo , Proteínas Reguladoras de Apoptose/metabolismo , Citocinas/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Vasculite/patologia
19.
Aging (Albany NY) ; 10(6): 1206-1222, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29883365

RESUMO

Copy number variations (CNVs) have been shown to cause numerous diseases, however, their roles in human lifespan remain elusive. In this study, we investigate the association of CNVs with longevity by comparing the Han Chinese genomes of long-lived individuals from 90 to 117 years of age and the middle-aged from 30 to 65. Our data demonstrate that the numbers of CNVs, especially deletions, increase significantly in a direct correlation with longevity. We identify eleven CNVs that strongly associate with longevity; four of them locate in the chromosome bands, 7p11.2, 20q13.33, 19p12 and 8p23.3 and overlap partially with the CNVs identified in long-lived Danish or U.S. populations, while the other seven have not been reported previously. These CNV regions encode nineteen known genes, and some of which have been shown to affect aging-related phenotypes such as the shortening of telomere length (ZNF208), the risk of cancer (FOXA1, LAMA5, ZNF716), and vascular and immune-related diseases (ARHGEF10, TOR2A, SH2D3C). In addition, we found several pathways enriched in long-lived genomes, including FOXA1 and FOXA transcription factor networks involved in regulating aging or age-dependent diseases such as cancer. Thus, our study has identified longevity-associated CNV regions and their affected genes and pathways. Our results suggest that the human genome structures such as CNVs might play an important role in determining a long life in human.

20.
BMC Biol ; 16(1): 44, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29706137

RESUMO

BACKGROUND: Intron retention (IR), the most prevalent alternative splicing form in plants, plays a critical role in gene expression during plant development and stress response. However, the molecular mechanisms underlying IR regulation remain largely unknown. RESULTS: Knockdown of SDG725, a histone H3 lysine 36 (H3K36)-specific methyltransferase in rice, leads to alterations of IR in more than 4700 genes. Surprisingly, IR events are globally increased at the 5' region but decreased at the 3' region of the gene body in the SDG725-knockdown mutant. Chromatin immunoprecipitation sequencing analyses reveal that SDG725 depletion results in a genome-wide increase of the H3K36 mono-methylation (H3K36me1) but, unexpectedly, promoter-proximal shifts of H3K36 di- and tri-methylation (H3K36me2 and H3K36me3). Consistent with the results in animals, the levels of H3K36me1/me2/me3 in rice positively correlate with gene expression levels, whereas shifts of H3K36me2/me3 coincide with position-specific alterations of IR. We find that either H3K36me2 or H3K36me3 alone contributes to the positional change of IR caused by SDG725 knockdown, although IR shift is more significant when both H3K36me2 and H3K36me3 modifications are simultaneously shifted. CONCLUSIONS: Our results revealed that SDG725 modulates IR in a position-specific manner, indicating that H3K36 methylation plays a role in RNA splicing, probably by marking the retained introns in plants.

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