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1.
Life Sci ; 264: 118560, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33045214

RESUMO

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of conditions ranging from hepatic steatosis to steatohepatitis (NASH) to fibrosis in the absence of alcohol consumption. Its pathogenesis involves both genetic and environmental factors with a multitude of underlying molecular mechanisms and mediators at each stage. Recent transcriptomic-based studies have led to the identification and association of long non-coding RNAs (lncRNAs) with disease pathology in NAFLD patients and in vivo rodent models. However, the knowledge of function of most of the lncRNAs in NAFLD pathology remains obscure. In the current review, we give a comprehensive catalogue of well reported lncRNAs in NAFLD and classify them using sequence and synteny-based evolutionary conservation across rodents, nonhuman primate and human species. The conserved lncRNAs across all the three species may be dissected in larger clinical studies of NAFLD and can be explored as biomarkers and therapeutic targets. In addition, we also review and analyse single nucleotide polymorphisms (SNPs) in these lncRNAs. It adds another facet to the regulatory role of NAFLD-associated lncRNAs and underscores the significance of a novel genetic landscape of non-coding genome in determining the genetic susceptibility of NAFLD.


Assuntos
Evolução Molecular , Hepatopatia Gordurosa não Alcoólica/genética , RNA Longo não Codificante/genética , Animais , Predisposição Genética para Doença/genética , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , RNA Longo não Codificante/metabolismo , Transcriptoma/genética
2.
Toxicol Lett ; 336: 21-31, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33069761

RESUMO

Hepatic fibrosis is the wound healing response upon the liver tissue damage caused by multiple stimuli. Targeting activated hepatic stellate cells (HSCs), the major extracellular matrix (ECM)-producing cells within the damaged liver, has been regarded as one of the main treatments for hepatic fibrosis. In the present study, we performed preliminary bioinformatics analysis attempting to identify possible factors related to hepatic fibrosis and found that lncRNA G protein-coupled receptor 137B (Gpr137b-ps) and C-X-C motif chemokine ligand 14 (CXCL14) showed to be markedly upregulated within carbon tetrachloride (CCl4)-caused hepatic fibrotic mice tissue samples and activated HSCs. CXCL14 The silencing of lncRNA Gpr137b-ps or CXCL14 alone could significantly improve CCl4-induced fibrotic changes in mice liver in vivo and collagen I and III release by HSCs and HSC proliferation in vitro. miR-200a-3p directly targeted lncRNA Gpr137b-ps and CXCL14, respectively. LncRNA Gpr137b-ps relieved miR-200a-3p-induced inhibition on CXCL14 expression via acting as a ceRNA. In HSCs, the effects of lncRNA Gpr137b-ps silencing on collagen I and III release by HSCs and HSC proliferation were significantly reversed by miR-200a-3p inhibition, and the effects of miR-200a-3p inhibition were reversed by CXCL14 silencing. In conclusion, we demonstrated a lncRNA Gpr137b-ps/miR-200a-3p/CXCL14 axis that modulates HSC activation and might exert an effect on the pathogenesis of liver fibrosis.


Assuntos
Proliferação de Células , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Quimiocinas CXC/metabolismo , Células Estreladas do Fígado/metabolismo , Cirrose Hepática Experimental/metabolismo , Fígado/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Tetracloreto de Carbono , Linhagem Celular , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Quimiocinas CXC/genética , Regulação da Expressão Gênica , Células Estreladas do Fígado/patologia , Fígado/patologia , Cirrose Hepática Experimental/induzido quimicamente , Cirrose Hepática Experimental/genética , Cirrose Hepática Experimental/patologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , RNA Longo não Codificante/genética , Transdução de Sinais
3.
Life Sci ; 264: 118656, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33121989

RESUMO

AIMS: Abnormal expression of long non-coding RNAs (lncRNAs) occurs in several diseases including renal fibrosis. Notably, growth arrest-specific 5 (Gas5) is a lncRNA, which functions as an essential modulator of cell proliferation and growth. However, the role and expression of lncRNA Gas5 associated with renal fibrosis remains controversial. Herein, we investigate the effect of lncRNA Gas5 deficiency in renal fibrosis induced by the operation of unilateral ureteric obstruction (UUO) in mice. MAIN METHODS: Sera and urine of mice were used to detect markers of renal function. Further, Masson and immunohistochemical staining, western blotting as well as qRT-PCR were performed to observe the distribution and expression of fibrosis marker in the kidney tissue of the mice. KEY FINDINGS: Unlike the wild type mice, the obstructed kidney in Gas5+/- mice showed more severe renal fibrosis and collagen deposition. In the UUO-Gas5+/- group, the serum levels of uric acid, serum creatinine, and the urine levels of albumin-to-creatinine ratio were higher. Moreover, the expression of mRNA and protein of α-smooth muscle actin (α-SMA), vimentin, collagen IV, fibronectin, and matrix metalloproteinase 9 (MMP9) were higher, whereas that of phosphatase and tensin homolog (PTEN) were lower with the difference being statistically significant (p < 0.05). SIGNIFICANCE: lncRNA Gas5 was up-regulated in renal fibrosis tissues, and its deficiency exacerbated renal fibrosis in the UUO mice model.


Assuntos
Rim/patologia , RNA Longo não Codificante/metabolismo , Obstrução Ureteral/genética , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Fibrose , Regulação da Expressão Gênica , Rim/fisiopatologia , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , PTEN Fosfo-Hidrolase/metabolismo , RNA Longo não Codificante/genética , Transdução de Sinais , Obstrução Ureteral/fisiopatologia
4.
Life Sci ; 264: 118665, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33127516

RESUMO

The incidence of cancer is growing worldwide, and it is becoming the most common cause of death. Long non-coding RNAs (lncRNAs) are a group of RNA transcripts with a length larger than 200 nucleotides that cannot encode proteins or peptides. LncRNAs regulate different biological functions by controlling gene expressions at transcriptional, translational, and post-translational levels. Non-coding RNA activated by DNA damage (NORAD) is a highly conserved lncRNA necessary for genome stability. LncRNA NORAD is dysregulated in various types of cancers. This biomarker has been involved in numerous processes associated with carcinogeneses, such as cell proliferation, apoptosis, invasion, and metastasis. In this paper, we reviewed the role of lncRNA NORAD and its biological functions in various human cancers to provide future research insights.


Assuntos
Neoplasias/genética , RNA Longo não Codificante/genética , Regulação Neoplásica da Expressão Gênica , Humanos , RNA Longo não Codificante/metabolismo
5.
Life Sci ; 264: 118728, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33160992

RESUMO

AIMS: Diabetic nephropathy (DN) is the most frequent complication of diabetes and causes millions of deaths each year. Finding novel therapy to DN is urgent, which requires a good understanding of the pathogenesis. Aims are to investigate the molecular mechanisms of DN by focusing on ANRIL/miR-497/TXNIP axis. MAIN METHODS: Kidney tissues were collected from diagnosed DN patients. High glucose (HG) treatment of human renal tubular epithelial cell cells (HK-2) was used as the cell model of DN. qRT-PCR and Western blotting were performed to measure levels of ANRIL, miR-497, TXNIP, IL-1ß, IL-18, caspase-1, and NLRP3. LDH leakage and cell viability were determined with commercial LDH activity kit and MTT assay. ELISA was employed to examine secreted IL-1ß and IL-18 levels. Flow cytometry was used to examine caspase-1 activity. Dual luciferase assay was performed to validate interactions of ANRIL/miR-497 and miR-497/TXNIP. KEY FINDINGS: ANRIL and TXNIP were elevated in DN kidney tissues and HG-treated HK-2 cells while miR-497 was reduced. ANRIL bound miR-497 while miR-497 directly targeted TXNIP. Knockdown of ANRIL suppressed HG-induced LDH leakage, TXNIP/NLRP3/caspase-1 activation, and increases of IL-1ß and IL-18 secreted levels. miR-497 knockdown or TXNIP overexpression reversed the effects of ANRIL knockdown on LDH leakage and pyroptosis-related signaling. miR-497 mimics inhibited caspase-1-dependent pyroptosis while co-overexpression of TXNIP blocked its effects in HG-treated HK-2 cells. SIGNIFICANCE: ANRIL promotes pyroptosis and kidney injury in DN via acting as miR-497 sponge to disinhibit TXNIP expression. These results shed light on the mechanisms of DN and provide targets for therapy development.


Assuntos
Proteínas de Transporte/metabolismo , Nefropatias Diabéticas/genética , MicroRNAs/metabolismo , Piroptose/genética , RNA Longo não Codificante/genética , Sequência de Bases , Proteínas de Transporte/genética , Caspase 1/metabolismo , Linhagem Celular , Técnicas de Silenciamento de Genes , Glucose/toxicidade , Humanos , MicroRNAs/genética , Modelos Biológicos , Piroptose/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , Transdução de Sinais/efeitos dos fármacos
6.
Life Sci ; 264: 118725, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33166593

RESUMO

AIMS: Long non-coding RNAs (lncRNAs) are associated with cancer development, while their relationship with the cancer-associated stromal components remains poorly understood. In this review, we performed a broad description of the functional landscape of stroma-associated lncRNAs in various cancers and their roles in regulating the tumor-stroma crosstalk. MATERIALS AND METHODS: We carried out a systematic literature review of PubMed, Scopus, Medline, Bentham, and EMBASE (Elsevier) databases by using the keywords "LncRNAs in cancer," "LncRNAs in tumor stroma," "stroma," "cancer-associated stroma," "stroma in the tumor microenvironment," "tumor-stroma crosstalk," "drug resistance of stroma," and "stroma in immunosuppression" till July 2020. We collected the latest articles addressing the biological functions of stroma-associated lncRNAs in cancer. KEY FINDINGS: These articles reported that dysregulated stroma-associated lncRNAs play significant roles in modulating the tumor microenvironment (TME) by the regulation of tumor-stroma crosstalk, epithelial to mesenchymal transition (EMT), endothelial to mesenchymal transition (EndMT), extracellular matrix (ECM) turnover, and tumor immunity. SIGNIFICANCE: The tumor stroma is a substantial portion of the TME, and the dysregulation of tumor stroma-associated lncRNAs significantly contributes to cancer initiation, progression, angiogenesis, immune evasion, metastasis, and drug resistance. Thus, stroma-associated lncRNAs could be potentially useful targets for cancer therapy.


Assuntos
Neoplasias/genética , Neoplasias/patologia , RNA Longo não Codificante/metabolismo , Transição Epitelial-Mesenquimal/genética , Humanos , Neovascularização Patológica/genética , RNA Longo não Codificante/genética , Células Estromais/metabolismo , Células Estromais/patologia , Microambiente Tumoral/genética
7.
Environ Sci Pollut Res Int ; 28(1): 587-596, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32816178

RESUMO

Arsenic is an environmental contaminant, its multiple effects on human tend to increase the rate of disease, cancer and other health problems. Some of long non-coding RNAs (lncRNAs) can be induced in major cellular processes such as necrosis, proliferation, and mutation. While the toxicity of arsenic is well established, the association between arsenic exposure and long non-coding RNAs has not been studied enough. This study investigated the association between arsenic and the expression of HOTAIR and LincRNA-p21 in vivo and vitro. In epidemiological studies, the expression of HOTAIR and LincRNA-p21 was increased after long-term arsenic exposure. HOTAIR and LincRNA-p21 expression were positively linked to monomethylarsenic acid (MMA), dimethylarsenic acid (DMA), inorganic arsenic (iAs), total arsenic (tAs), and MMA% and negatively linked to secondary methylation index (SMI). In A549 cells, arsenic exposure resulted in enhanced HOTAIR and LincRNA-p21 expression dose-dependently. The expression of HOTAIR was considerably high in the presence of NaAsO2 and MMA but showed no difference in DMA compared with control group. And LincRNA-p21 expression was increased in the presence of NaAsO2, MMA, and DMA. The expression of HOTAIR and LincRNA-p21 induced by iAs was much higher than that induced by MMA and DMA. Compared with the control group, treatment of A549 cells with NaAsO2/S-adenosylmethionine (SAM) and NaAsO2/glutathione (GSH) combination increased HOTAIR and LincRNA-p21 expression. The expression of LincRNA-p21 in combination of NaAsO2/GSH was significantly decreased compared with NaAsO2 alone. Besides, in the presence of arsenic, both of HOTAIR and LincRNA-p21 were upregulated significantly when P53 was knocked down. We revealed that inorganic arsenic, its methylated metabolites, and arsenic metabolism efficiency affect the expression of HOTAIR and LincRNA-p21.


Assuntos
Arsênico , Arsenicais , RNA Longo não Codificante , Arsênico/análise , Ácido Cacodílico , Exposição Ambiental , Humanos , Metilação , RNA Longo não Codificante/genética
8.
Ecotoxicol Environ Saf ; 208: 111424, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33120262

RESUMO

Emerging evidences having suggested that particular lncRNAs have a potential effect on PD progression through provoking damage and inflammatory responses of microglia/ dopaminergic cells. In addition, paraquat can be accumulated in human body through various approaches and have an increased risk for Parkinson's disease. However, the specific role and mechanism of lncRNA related to neurotoxic in the progression of PD is unclear. In our study, a mouse PD model was established induced by the intraperitoneal injection of paraquat (5 mg/kg and 10 mg/kg) every three days (10 times). We determined differential expression of lncRNA AK039862 and its potential targeted genes Pafah1b1/Foxa1 in PD mouse model, then we used fluorescence in situ hybridization (FISH) to visualize the cellular distribution of AK039862. Short interfering RNAs (siRNAs) and overexpression plasmids were designed for knockdown or overexpression of AK039862. To simulate the coexisting dopaminergic cells and microglia cells in vitro, we applied several non-contact co-culture models, including conditioned medium and Transwell co-culture systems. Cytotoxicity of PQ was evaluated using bv2 cells with the concentrations: 30, 60 µM, and mn9d cells with the concentrations: 50, 100 µM. As a result, we depicted multiple interesting individual and interactive features of inflammatory lncRNA AK039862 involved in PQ-induced cellular functional effects. First, we detected that AK039862 contributed to the neuronal injury process in PQ-treated mice and co-localization of AK039862 with dopaminergic cells in vivo. And interestingly, we demonstrated that PQ significantly inhibited microglia and dopaminergic cells proliferation and microglia migration in vitro. Further research indicated that the PQ-induced low expression of AK039862 rescued microglia proliferation and migration inhibition via the AK039862/Pafah1b1/Foxa1 pathway. Meanwhile, AK039862 also participated in the interaction between microglia and dopaminergic cells with PQ treatment in non-contact co-culture models. In summary, we found that PQ inhibited the proliferation and migration of microglial cells, and elucidated AK039862 played a key role in PQ-induced neuroinflammatory damage through Pafah1b1/Foxa1. Finally, inflammatory AK039862 is involved in the complex communication between microglia and dopaminergic cells in the environment of PQ damage.


Assuntos
Herbicidas/toxicidade , Paraquat/toxicidade , RNA Longo não Codificante/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterase/farmacologia , Animais , Proliferação de Células , Técnicas de Cocultura , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Fator 3-alfa Nuclear de Hepatócito/farmacologia , Hibridização in Situ Fluorescente , Masculino , Camundongos , Microglia/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Síndromes Neurotóxicas/metabolismo
9.
J Surg Res ; 257: 501-510, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32916503

RESUMO

BACKGROUND: Breast cancer is a familiar malignant tumor, which is a great threat to women's life. Long noncoding RNA Opa interacting protein 5-antisense RNA 1 (OIP5-AS1) has been reported to be associated with numerous cancers. This study aimed to explore the role of OIP5-AS1 and the mechanism of its action in the progression of breast cancer. METHODS: The expression of OIP5-AS1 and miR-216a-5p was detected by quantitative real-time polymerase chain reaction. Cell proliferation, apoptosis, migration, or invasion was assessed by 4-5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, flow cytometry, or transwell assay, respectively. The binding sites were predicted by bioinformatics tool starBase2.0 (http://starbase.sysu.edu.cn/starbase2/index.php). The interaction between miR-216a-5p and OIP5-AS1 or glyoxalase 1 (GLO1) was confirmed by dual-luciferase reporter assay. The expression of GLO1 was quantified by Western blot. Nude mouse tumorigenicity assays were conducted to verify the role of OIP5-AS1 in vivo. RESULTS: OIP5-AS1 and GLO1 were highly expressed in both clinical tumor tissues and cell lines, whereas miR-216a-5p was downregulated. Knockdown of OIP5-AS1 suppressed proliferation, migration, and invasion but promoted apoptosis of breast cancer cells. MiR-216a-5p was a target of OIP5-AS1 and interacted with GLO1. MiR-216a-5p inhibition or GLO1 overexpression reversed the effects of OIP5-AS1 knockdown on the development of breast cancer cells. OIP5-AS1 knockdown depleted tumor growth in vivo. CONCLUSIONS: OIP5-AS1 knockdown suppressed the progression of breast cancer by inducing GLO1 expression via competitively binding to miR-216a-5p, suggesting that OIP5-AS1 was a hopeful biomarker for the therapy of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Lactoilglutationa Liase/metabolismo , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Humanos , Camundongos Nus
10.
Environ Pollut ; 268(Pt A): 115810, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33162208

RESUMO

Arsenic is a potent toxicant, and long-term exposure to inorganic arsenic causes lung damage. M2 macrophages play an important role in the pathogenesis of pulmonary fibrosis. However, the potential connections between arsenic and M2 macrophages in the development of pulmonary fibrosis are elusive. C57BL/6 mice were fed with drinking water containing 0, 10 and 20 ppm arsenite for 12 months. We have found that, in lung tissues of mice, arsenite, a biologically active form of arsenic, elevated H19, c-Myc, and Arg1; decreased let-7a; and caused pulmonary fibrosis. For THP-1 macrophages (THP-M) and bone-marrow-derived macrophages (BMDMs), 8 µM arsenite increased H19, c-Myc, and Arg1; decreased let-7a; and induced M2 polarization of macrophages, which caused secretion of the fibrogenic cytokine, TGF-ß1. Down-regulation of H19 or up-regulation of let-7a reversed the arsenite-induced M2 polarization of macrophages. Arsenite-treated THP-M and BMDMs co-cultured with MRC-5 cells or primary lung fibroblasts (PLFs) elevated levels of p-SMAD2/3, SMAD4, α-SMA, and collagen I in lung fibroblasts and resulted in the activation of lung fibroblasts. Knockout of H19 or up-regulation of let-7a in macrophages reversed the effects. The results indicated that H19 functioned as an miRNA sponge for let-7a, which was involved in arsenite-induced M2 polarization of macrophages and induced the myofibroblast differentiation phenotype by regulation of c-Myc. In the sera of arseniasis patients, levels of hydroxyproline and H19 were higher, and levels of let-7a were lower than levels in the controls. These observations elucidate a possible mechanism for arsenic exposure-induced pulmonary fibrosis.


Assuntos
Arsênico , MicroRNAs , Fibrose Pulmonar , RNA Longo não Codificante , Animais , Arsênico/toxicidade , Diferenciação Celular , Humanos , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Miofibroblastos , Fibrose Pulmonar/induzido quimicamente , RNA Longo não Codificante/genética
11.
Cardiovasc Ther ; 2020: 5925342, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33294032

RESUMO

Several studies have indicated that long noncoding RNAs (lncRNAs)-HOX transcript antisense RNA (HOTAIR) is involved in some cardiovascular diseases by regulating gene expression as a competitive endogenous RNA (ceRNA). GJA1 encoding Cx43 is one potential target gene of microRNA-613 (miR-613). Meanwhile, there is a potential target regulatory relationship between HOTAIR and miR-613. The present study is aimed at investigating whether HOTAIR functions as a ceRNA to regulate the Cx43 expression in atrial fibrillation (AF) by sponging miR-613. The expressions of HOTAIR, miR-613, and Cx43 were detected in the right atrial appendages of 45 patients with heart valve disease, including 23 patients with chronic AF. The HOTAIR overexpressed and underexpressed HL-1 cell model were constructed to confirm the effect of HOTAIR on Cx43. Then, the Cx43 expression was detected to testify the interplay between HOTAIR and miR-613 after cotransfecting HOTAIR and miR-613. Furthermore, luciferase assays were performed to verify that HOTAIR could regulate Cx43 remolding as a ceRNA by sponging miR-613. The expression of HOTAIR and Cx43 was significantly downregulated in chronic AF group. HOTAIR regulated positively the Cx43 expression in HL-1 cells. The upregulated effect of HOTAIR on the Cx43 expression could be remarkably attenuated by miR-613. Moreover, the inhibitory effect of miR-613 on the Cx43 expression could be obviously mitigated by HOTAIR. At last, luciferase assays confirmed HOTAIR functioned as a ceRNA in the Cx43 expression by sponging miR-613. Our study suggests that HOTAIR, functioning as a ceRNA by sponging miR-613, is an important contributor to Cx43 remolding in AF.


Assuntos
Apêndice Atrial/metabolismo , Fibrilação Atrial/metabolismo , Remodelamento Atrial , Conexina 43/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/metabolismo , Adulto , Idoso , Animais , Apêndice Atrial/fisiopatologia , Fibrilação Atrial/genética , Fibrilação Atrial/fisiopatologia , Linhagem Celular , Conexina 43/genética , Feminino , Regulação da Expressão Gênica , Frequência Cardíaca , Humanos , Masculino , Camundongos , MicroRNAs/genética , Pessoa de Meia-Idade , RNA Longo não Codificante/genética , Transdução de Sinais
12.
Int J Nanomedicine ; 15: 10305-10320, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33376323

RESUMO

Purpose: The clinical management of patients with castration-resistant prostate cancer (CRPC) is difficult. However, novel treatment methods are gradually being introduced. Considering the adverse effects of traditional treatments, recent studies have investigated gene therapy as a method to combat CRPC; but, the application of long non-coding (lnc) RNA in gene therapy remains scarce, despite their promise. Therefore, it is imperative to develop a system that can efficiently deliver lncRNA for the treatment of CRPC. Here, we investigated the efficacy of a delivery system by introducing the plasmid-encoding tumor suppressor lncRNA MEG3 (pMEG3) in CRPC cells. Materials and Methods: An EpDT3 aptamer-linked poly(amidoamine) (PAMAM) dendrimer targeting EpCAM was used to deliver pMEG3 in CRPC cells. The PAMAM-PEG-EpDT3/pMEG3 nanoparticles (NPs) were tested using in vitro cellular assays including cellular uptake, entry, and CCK-8 measurement, and tumor growth inhibition, histological assessment, and safety evaluations in in vivo animal models. Results: The EpDT3 aptamer promoted endocytosis of PAMAM and PAMAM-PEG-EpDT3/pMEG3 NPs in CRPC cells. PAMAM-PEG-EpDT3/pMEG3 NPs exhibited a significant anti-CRPC effect, both in vivo and in vitro, when compared to that of unfunctionalized PAMAM-PEG/pMEG3 NPs. Conclusion: PAMAM-PEG-EpDT3/pMEG3 NPs can potentially improve gene therapy in CRPC cells.


Assuntos
Aptâmeros de Nucleotídeos/química , Dendrímeros/química , Terapia Genética/métodos , Plasmídeos/genética , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/terapia , RNA Longo não Codificante/genética , Animais , Linhagem Celular Tumoral , Portadores de Fármacos/química , Humanos , Masculino , Nanopartículas/química , Plasmídeos/química , Polietilenoglicóis/química
13.
BMC Bioinformatics ; 21(1): 555, 2020 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-33267800

RESUMO

BACKGROUND: Accumulating evidence has demonstrated that long non-coding RNAs (lncRNAs) are closely associated with human diseases, and it is useful for the diagnosis and treatment of diseases to get the relationships between lncRNAs and diseases. Due to the high costs and time complexity of traditional bio-experiments, in recent years, more and more computational methods have been proposed by researchers to infer potential lncRNA-disease associations. However, there exist all kinds of limitations in these state-of-the-art prediction methods as well. RESULTS: In this manuscript, a novel computational model named FVTLDA is proposed to infer potential lncRNA-disease associations. In FVTLDA, its major novelty lies in the integration of direct and indirect features related to lncRNA-disease associations such as the feature vectors of lncRNA-disease pairs and their corresponding association probability fractions, which guarantees that FVTLDA can be utilized to predict diseases without known related-lncRNAs and lncRNAs without known related-diseases. Moreover, FVTLDA neither relies solely on known lncRNA-disease nor requires any negative samples, which guarantee that it can infer potential lncRNA-disease associations more equitably and effectively than traditional state-of-the-art prediction methods. Additionally, to avoid the limitations of single model prediction techniques, we combine FVTLDA with the Multiple Linear Regression (MLR) and the Artificial Neural Network (ANN) for data analysis respectively. Simulation experiment results show that FVTLDA with MLR can achieve reliable AUCs of 0.8909, 0.8936 and 0.8970 in 5-Fold Cross Validation (fivefold CV), 10-Fold Cross Validation (tenfold CV) and Leave-One-Out Cross Validation (LOOCV), separately, while FVTLDA with ANN can achieve reliable AUCs of 0.8766, 0.8830 and 0.8807 in fivefold CV, tenfold CV, and LOOCV respectively. Furthermore, in case studies of gastric cancer, leukemia and lung cancer, experiment results show that there are 8, 8 and 8 out of top 10 candidate lncRNAs predicted by FVTLDA with MLR, and 8, 7 and 8 out of top 10 candidate lncRNAs predicted by FVTLDA with ANN, having been verified by recent literature. Comparing with the representative prediction model of KATZLDA, comparison results illustrate that FVTLDA with MLR and FVTLDA with ANN can achieve the average case study contrast scores of 0.8429 and 0.8515 respectively, which are both notably higher than the average case study contrast score of 0.6375 achieved by KATZLDA. CONCLUSION: The simulation results show that FVTLDA has good prediction performance, which is a good supplement to future bioinformatics research.


Assuntos
Biologia Computacional/métodos , Simulação por Computador , Doença/genética , RNA Longo não Codificante/genética , Humanos , Neoplasias/genética , Redes Neurais de Computação , Fatores de Risco
14.
Medicine (Baltimore) ; 99(49): e23209, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33285697

RESUMO

Intracranial aneurysm (IA) is one of the main causes of subarachnoid hemorrhage (SAH) leading to a high percentage of disability and mortality worldwide. In addition to environmental factors, the risk of rupture or prognosis of intracranial aneurysm is also closely related to gene. Thus, a lot of genetic studies have been used to explore associated risk genes as well as variant loci of intracranial aneurysm and found several chromosome variates including 9p21.3 (CDKN2BAS) related to Intracranial aneurysm. However, due to differences in population and the existence of SNP, it is still not determined that whether these genetic changes can be identified as independent risk factors for intracranial aneurysm. Therefore, we performed a meta-analysis of CDKN2BAS SNPs to explore its association with intracranial aneurysms and the results show a significance relation between rs10757272, rs1333040, and rs6475606 with intracranial aneurysm. This will open a new perspective for future intracranial aneurysm gene research and therapy.


Assuntos
Inibidor de Quinase Dependente de Ciclina p15/genética , Aneurisma Intracraniano/genética , RNA Longo não Codificante/genética , Humanos , Polimorfismo de Nucleotídeo Único
15.
Nat Commun ; 11(1): 6135, 2020 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-33262333

RESUMO

Long non-coding RNAs (lncRNAs) are emerging regulators of pathophysiological processes including atherosclerosis. Using RNA-seq profiling of the intima of lesions, here we identify a macrophage-specific lncRNA MAARS (Macrophage-Associated Atherosclerosis lncRNA Sequence). Aortic intima expression of MAARS increases by 270-fold with atherosclerotic progression and decreases with regression by 60%. MAARS knockdown reduces atherosclerotic lesion formation by 52% in LDLR-/- mice, largely independent of effects on lipid profile and inflammation, but rather by decreasing macrophage apoptosis and increasing efferocytosis in the vessel wall. MAARS interacts with HuR/ELAVL1, an RNA-binding protein and important regulator of apoptosis. Overexpression and knockdown studies verified MAARS as a critical regulator of macrophage apoptosis and efferocytosis in vitro, in an HuR-dependent manner. Mechanistically, MAARS knockdown alters HuR cytosolic shuttling, regulating HuR targets such as p53, p27, Caspase-9, and BCL2. These findings establish a mechanism by which a macrophage-specific lncRNA interacting with HuR regulates apoptosis, with implications for a broad range of vascular disease states.


Assuntos
Aterosclerose/metabolismo , Núcleo Celular/metabolismo , Proteína Semelhante a ELAV 1/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Apoptose , Aterosclerose/genética , Aterosclerose/fisiopatologia , Núcleo Celular/genética , Proteína Semelhante a ELAV 1/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Transporte Proteico , RNA Longo não Codificante/genética , Especificidade da Espécie
16.
Signal Transduct Target Ther ; 5(1): 294, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-33361761

RESUMO

Understanding the processes of immune regulation in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for improving treatment. Here, we performed longitudinal whole-transcriptome RNA sequencing on peripheral blood mononuclear cell (PBMC) samples from 18 patients with coronavirus disease 2019 (COVID-19) during their treatment, convalescence, and rehabilitation. After analyzing the regulatory networks of differentially expressed messenger RNAs (mRNAs), microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) between the different clinical stages, we found that humoral immunity and type I interferon response were significantly downregulated, while robust T-cell activation and differentiation at the whole transcriptome level constituted the main events that occurred during recovery from COVID-19. The formation of this T cell immune response might be driven by the activation of activating protein-1 (AP-1) related signaling pathway and was weakly affected by other clinical features. These findings uncovered the dynamic pattern of immune responses and indicated the key role of T cell immunity in the creation of immune protection against this disease.


Assuntos
/genética , Imunidade Humoral/genética , Linfócitos T/metabolismo , Transcriptoma/genética , /epidemiologia , Feminino , Humanos , Imunidade Humoral/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , MicroRNAs , RNA Longo não Codificante/genética , RNA-Seq , /patogenicidade , Linfócitos T/imunologia , Linfócitos T/patologia , Fator de Transcrição AP-1/genética
17.
Nat Commun ; 11(1): 6348, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33311506

RESUMO

Long non-coding RNAs are important regulators of biological processes including immune responses. The immunoregulatory functions of lncRNAs have been revealed primarily in murine models with limited understanding of lncRNAs in human immune responses. Here, we identify lncRNA LUCAT1 which is upregulated in human myeloid cells stimulated with lipopolysaccharide and other innate immune stimuli. Targeted deletion of LUCAT1 in myeloid cells increases expression of type I interferon stimulated genes in response to LPS. By contrast, increased LUCAT1 expression results in a reduction of the inducible ISG response. In activated cells, LUCAT1 is enriched in the nucleus where it associates with chromatin. Further, LUCAT1 limits transcription of interferon stimulated genes by interacting with STAT1 in the nucleus. Together, our study highlights the role of the lncRNA LUCAT1 as a post-induction feedback regulator which functions to restrain the immune response in human cells.


Assuntos
Regulação da Expressão Gênica , Interferons/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Animais , Fenômenos Biológicos , Cromatina/metabolismo , Citocinas/metabolismo , Retroalimentação , Técnicas de Silenciamento de Genes , Humanos , Imunidade Inata/efeitos dos fármacos , Lipopolissacarídeos/efeitos adversos , Camundongos , Células Mieloides/metabolismo , Proteínas , Fator de Transcrição STAT1/metabolismo , Células THP-1
18.
Medicine (Baltimore) ; 99(50): e23444, 2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33327275

RESUMO

This study aimed to investigate the correlation of long non-coding RNA taurine upregulated gene 1 (lncRNA TUG1) with microRNA-223 (miR-223) as well as their associations with risk, severity, and mortality of sepsis.Totally122 sepsis patients and 122 healthy controls were enrolled. Plasma lncRNA TUG1 and miR-223 levels were detected by reverse transcription quantitative polymerase chain reaction. General severity of sepsis was assessed within 24 hours after admission using acute pathologic and chronic health evaluation (APACHE) II score and sequential organ failure assessment (SOFA) score. Patients were intensively followed up until death or 28 days after enrollment to assess mortality.LncRNA TUG1 expression was decreased (P < .001) but miR-223 expression (P < .001) was elevated in sepsis patients. Additionally, a negative correlation of lncRNA TUG1 expression with miR-223 expression was observed in sepsis patients (P < .001). Moreover, in sepsis patients, lncRNA TUG1 expression was negatively correlated with respiratory infection, serum creatinine (Scr), white blood cell (WBC), C-reactive protein (CRP), APACHE II score, and SOFA score but positively correlated with albumin (all P < .05); miR-223 expression was negatively correlated with skin and soft tissue infection and albumin but positively correlated with Scr, WBC, CRP, APACHE II score, and SOFA score (all P < 0.05). As to mortality, lncRNA TUG1 expression was decreased (P = .001) but miR-223 was elevated (P < .001) in 28-day sepsis deaths compared with 28-day sepsis survivors.Our findings offer the potential of lncRNA TUG1 and miR-223 as biomarkers for progression and prognosis of sepsis.


Assuntos
MicroRNAs/sangue , RNA Longo não Codificante/sangue , Sepse/genética , Sepse/mortalidade , APACHE , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Marcadores Genéticos , Humanos , Masculino , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Fatores de Risco , Taxa de Sobrevida
19.
Med Sci Monit ; 26: e927725, 2020 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-33328429

RESUMO

BACKGROUND Long non-coding RNA (lncRNA) can act as competing endogenous RNA (ceRNA) during tumor development. However, no study has elucidated the ceRNA network in pediatric rhabdoid tumor of the kidney (RTK) and its prognostic-related lncRNAs. The goal of the present study was to identify potential biomarkers of prognostic-related lncRNAs. MATERIAL AND METHODS RNA sequencing and clinical data were procured from the TARGET database. The "EdgeR" package was used to obtain differentially expressed lncRNA (DElncRNA), differentially expressed messenger RNAs (DEmRNA), and differentially expressed microRNAs (DEmiRNA). Cytoscape software was used to construct a ceRNA network. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were conducted on the ceRNA network-related DEmRNA. The Kaplan-Meier method was used for predicting survival with ceRNA network-related DElncRNA. Univariate and multivariate Cox analyses were used to identify prognosis-related lncRNAs in the ceRNA network, and an RTK prognostic signature was constructed. RESULTS We identified 1109 DElncRNAs, 215 DEmiRNAs, and 3436 DEmRNAs; and 107 DElncRNAs, 21 DEmiRNAs, and 74 DEmRNAs were included in the ceRNA regulatory network. GO enrichment analysis and KEGG pathway enrichment indicated that the DEmRNAs were mainly related to the regulation of phospholipase C activity and the MAPK signaling pathway. Survival analysis showed that 9 of 107 DElncRNAs were correlated with prognosis (P<0.05). Univariate and multivariate Cox analysis identified 4 DElncRNAs (HNF1A-AS1, TPTEP1, SNHG6, and ZNF503-AS2) to establish a predictive model and can be used as independent prognostic biomarkers. CONCLUSIONS We constructed a ceRNA network that reveals potential lncRNA biomarkers for pediatric RTK.


Assuntos
Estimativa de Kaplan-Meier , Neoplasias Renais , RNA Longo não Codificante/análise , Tumor Rabdoide , Biomarcadores Tumorais/análise , Criança , Bases de Dados Genéticas , Humanos , Neoplasias Renais/diagnóstico , Neoplasias Renais/genética , Prognóstico , Modelos de Riscos Proporcionais , Proteínas Repressoras , Tumor Rabdoide/diagnóstico , Tumor Rabdoide/genética
20.
Medicine (Baltimore) ; 99(49): e23522, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33285765

RESUMO

BACKGROUND: Long non-coding RNA (lncRNA) can predict the prognosis of patients with various cancers. The relationship between lncRNA taurine upregulated gene 1 (TUG1) and the prognosis of patients with gastric carcinoma still needs to be further explored. Therefore, this study attempted to explore the relationship between TUG1 and the prognosis of patients suffering from gastric carcinoma. METHODS: The database was retrieved from China National Knowledge Infrastructure (CNKI), Chinese Biomedical literature Database (CBM), Chinese Scientific and Journal Database (VIP), Wan Fang database, PubMed, and EMBASE. Hazard ratios (HRs) and its 95% confidence interval (CIs) were applied to assess the prognostic effects of TUG1 on overall survival (OS). RevMan 5.3 software was adopted to perform meta-analysis. RESULTS: The results of this meta-analysis would be submitted to peer-reviewed journals for publication. CONCLUSION: This review provided a comprehensive overview of the relationship between TUG1 and the prognosis of patients with gastric carcinoma, and offered recommendations for clinical practices or guidelines.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma/genética , RNA Longo não Codificante/análise , Neoplasias Gástricas/genética , Carcinoma/mortalidade , Humanos , Metanálise como Assunto , Valor Preditivo dos Testes , Prognóstico , Projetos de Pesquisa , Neoplasias Gástricas/mortalidade , Revisões Sistemáticas como Assunto
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