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1.
EMBO Rep ; : e52901, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34523214

RESUMO

Cardiac regeneration occurs primarily through proliferation of existing cardiomyocytes, but also involves complex interactions between distinct cardiac cell types including non-cardiomyocytes (non-CMs). However, the subpopulations, distinguishing molecular features, cellular functions, and intercellular interactions of non-CMs in heart regeneration remain largely unexplored. Using the LIGER algorithm, we assemble an atlas of cell states from 61,977 individual non-CM scRNA-seq profiles isolated at multiple time points during regeneration. This analysis reveals extensive non-CM cell diversity, including multiple macrophage (MC), fibroblast (FB), and endothelial cell (EC) subpopulations with unique spatiotemporal distributions, and suggests an important role for MC in inducing the activated FB and EC subpopulations. Indeed, pharmacological perturbation of MC function compromises the induction of the unique FB and EC subpopulations. Furthermore, we developed computational algorithm Topologizer to map the topological relationships and dynamic transitions between functional states. We uncover dynamic transitions between MC functional states and identify factors involved in mRNA processing and transcriptional regulation associated with the transition. Together, our single-cell transcriptomic analysis of non-CMs during cardiac regeneration provides a blueprint for interrogating the molecular and cellular basis of this process.

2.
Int J Mol Sci ; 22(16)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445647

RESUMO

Unveiling the molecular features in the heart is essential for the study of heart diseases. Non-cardiomyocytes (nonCMs) play critical roles in providing structural and mechanical support to the working myocardium. There is an increasing amount of single-cell RNA-sequencing (scRNA-seq) data characterizing the transcriptomic profiles of nonCM cells. However, no tool allows researchers to easily access the information. Thus, in this study, we develop an open-access web portal, ExpressHeart, to visualize scRNA-seq data of nonCMs from five laboratories encompassing three species. ExpressHeart enables comprehensive visualization of major cell types and subtypes in each study; visualizes gene expression in each cell type/subtype in various ways; and facilitates identifying cell-type-specific and species-specific marker genes. ExpressHeart also provides an interface to directly combine information across datasets, for example, generating lists of high confidence DEGs by taking the intersection across different datasets. Moreover, ExpressHeart performs comparisons across datasets. We show that some homolog genes (e.g., Mmp14 in mice and mmp14b in zebrafish) are expressed in different cell types between mice and zebrafish, suggesting different functions across species. We expect ExpressHeart to serve as a valuable portal for investigators, shedding light on the roles of genes on heart development in nonCM cells.


Assuntos
Células Endoteliais/metabolismo , Fibroblastos/metabolismo , Ventrículos do Coração/metabolismo , Internet , Macrófagos/metabolismo , Pericitos/metabolismo , Transcriptoma , Algoritmos , Animais , Perfilação da Expressão Gênica , Humanos , Camundongos , Análise de Sequência de RNA , Análise de Célula Única , Software , Peixe-Zebra
3.
Front Oncol ; 11: 651915, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34249688

RESUMO

Although the importance of PIWI-interacting RNAs (piRNAs) in cancer has recently been recognized, studies on the role and functional mechanism of piRNAs in lung adenocarcinoma (LUAD) development and progression are limited. In this study, we identified 10 differently expressed piRNAs in LUAD tissues compared to normal tissues, among which, piR-hsa-211106 expression levels were downregulated in LUAD tissues and cell lines. Furthermore, the effects of piR-hsa-211106 on the malignant phenotypes and chemosensitivity of LUAD cells were detected by gain- and loss-of-function analyses in vitro and in vivo, which showed that piR-hsa-211106 inhibited LUAD cell proliferation, tumor growth, and migration, but promoted apoptosis. Moreover, our finding indicated that piR-hsa-211106 is a potential therapeutic target that synergistically imparts anticancer effects with a chemotherapeutic agent for LUAD-cisplatin. Further mechanistic investigation indicated that piR-hsa-211106 could bind to pyruvate carboxylase (PC) by RNA pull down and RNA immunoprecipitation assays and inhibited PC mRNA and protein expression. Our study demonstrates that piR-hsa-211106 inhibits LUAD progression by hindering the expression and function of PC and enhances chemotherapy sensitivity, suggesting that piR-hsa-211106 is a novel diagnostic and therapeutic target for LUAD.

4.
Semin Cell Dev Biol ; 118: 144-149, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33994094

RESUMO

Heart malformation is the leading cause of human birth defects, and many of the congenital heart diseases (CHDs) originate from genetic defects that impact cardiac development and maturation. During development, the vertebrate heart undergoes a series of complex morphogenetic processes that increase its ability to pump blood. One of these processes leads to the formation of the sheet-like muscular projections called trabeculae. Trabeculae increase cardiac output and permit nutrition and oxygen uptake in the embryonic myocardium prior to coronary vascularization without increasing heart size. Cardiac trabeculation is also crucial for the development of the intraventricular fast conduction system. Alterations in cardiac trabecular development can manifest as a variety of congenital defects such as left ventricular noncompaction. In this review, we discuss the latest advances in understanding the molecular and cellular mechanisms underlying cardiac trabecular development.

5.
Int J Biol Sci ; 17(2): 562-573, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33613113

RESUMO

Identifying high specificity and sensitivity biomarkers has always been the focus of research in the field of non-invasive cancer diagnosis. Exosomes are extracellular vesicles with a lipid bilayer membrane that can be released by all types of cells, which contain a variety of proteins, lipids, and a variety of non-coding RNAs. Increasing research has shown that the lipid bilayer can effectively protect the nucleic acid in exosomes. In cancers, tumor cell-derived exosomal circRNAs can act on target cells or organs through the transport of exosomes, and then participate in the regulation of tumor development and metastasis. Since exosomes exist in various body fluids and circRNAs in exosomes exhibit high stability, exosomal circRNAs have the potential as biomarkers for early and minimally invasive cancer diagnosis and prognosis judgment. In this review, we summarized circRNAs and their biological roles in cancers, with the emerging value biomarkers in cancer diagnosis, disease judgment, and prognosis observation. In addition, we briefly compared the advantages of exosomal circRNAs as biomarkers and the current obstacles in the exosome isolation technology, shed light to the future development of this technology.

6.
Plant Dis ; : PDIS06201218RE, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33258433

RESUMO

Photinia (Photinia × fraseri Dress) is a well-known green plant that has high ornamental value and is widely distributed around the world. An outbreak of typical bud blight disease was observed between May and August in photinia in 2017 in Qingdao, China. The causal agent for this blight was subsequently isolated from symptomatic samples and identified as Nothophoma quercina based on morphological characterization and molecular analyses (ITS, LSU, RPB2, and TUB2). Results of pathogenicity tests on isolated fungi also supported the conclusion that N. quercina is the pathogen responsible for this condition. To our knowledge, this is the first report of bud blight on P. fraseri caused by N. quercina in China.

7.
Phytopathology ; 2020 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-33289404

RESUMO

Tetrandrine (TET) is a potent calcium channel blocker used for the treatment of hypertension and inflammation. Currently, TET is predominantly used to treat a variety of human diseases, and there is little information regarding the use of TET against plant pathogens. In this study, we explored the antifungal activity of TET on a plant pathogen, Botrytis cinerea. We show that administration of low concentrations of TET effectively inhibited hyphal growth of fungus grown on potato dextrose agarose, and decreased the virulence of B. cinerea in tomato plants. Real-time PCR revealed that the expression of drug efflux pump related genes (alcohol dehydrogenase 1, multi-drug/pheromone exporter, pleiotropic drug resistance protein 1, and synaptic vesicle transporter) were down-regulated in the presence of TET. Finally, we show that TET acts synergistically with iprodione, resulting in increased inhibition of B. cinerea both in vitro and in vivo. These results indicate that TET might act as an effective antifungal agent in reducing grey mold disease.

8.
Oxid Med Cell Longev ; 2020: 5860356, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33282111

RESUMO

Reduction oxidation (REDOX) reaction is crucial in life activities, and its dynamic balance is regulated by ROS. Reactive oxygen species (ROS) is associated with a variety of metabolic diseases involving in multiple cellular signalling in pathologic and physiological signal transduction. ROS are the by-products of numerous enzymatic reactions in various cell compartments, including the cytoplasm, cell membrane, endoplasmic reticulum (ER), mitochondria, and peroxisome. ROS signalling is not only involved in normal physiological processes but also causes metabolic dysfunction and maladaptive responses to inflammatory signals, which depends on the cell type or tissue environment. Excess oxidants are able to alter the normal structure and function of DNA, lipids, and proteins, leading to mutations or oxidative damage. Therefore, excessive oxidative stress is usually regarded as the cause of various pathological conditions, such as cancer, neurodegeneration, cardiovascular diseases (CVDs), diabetes, and kidney diseases. Currently, it has been possible to detect diabetes and other cardiac diseases by detecting derivatives accompanied by oxidative stress in vivo as biomarkers, but there is no effective method to treat these diseases. In consequence, it is essential for us to seek new therapy targeting these diseases through understanding the role of ROS signalling in regulating metabolic activity, inflammatory activation, and cardiac diseases related to metabolic dysfunction. In this review, we summarize the current literature on REDOX and its role in the regulation of cardiac metabolism and inflammation, focusing on ROS, local REDOX signalling pathways, and other mechanisms.


Assuntos
Doenças Cardiovasculares/metabolismo , Mitocôndrias/efeitos dos fármacos , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Animais , Doenças Cardiovasculares/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos
9.
Nat Cell Biol ; 22(11): 1319-1331, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33020597

RESUMO

PIWI-interacting RNAs (piRNAs) are abundantly expressed during cardiac hypertrophy. However, their functions and molecular mechanisms remain unknown. Here, we identified a cardiac-hypertrophy-associated piRNA (CHAPIR) that promotes pathological hypertrophy and cardiac remodelling by targeting METTL3-mediated N6-methyladenosine (m6A) methylation of Parp10 mRNA transcripts. CHAPIR deletion markedly attenuates cardiac hypertrophy and restores heart function, while administration of a CHAPIR mimic enhances the pathological hypertrophic response in pressure-overloaded mice. Mechanistically, CHAPIR-PIWIL4 complexes directly interact with METTL3 and block the m6A methylation of Parp10 mRNA transcripts, which upregulates PARP10 expression. The CHAPIR-dependent increase in PARP10 promotes the mono-ADP-ribosylation of GSK3ß and inhibits its kinase activity, which results in the accumulation of nuclear NFATC4 and the progression of pathological hypertrophy. Hence, our findings reveal that a piRNA-mediated RNA epigenetic mechanism is involved in the regulation of cardiac hypertrophy and that the CHAPIR-METTL3-PARP10-NFATC4 signalling axis could be therapeutically targeted for treating pathological hypertrophy and maladaptive cardiac remodelling.


Assuntos
Adenosina/análogos & derivados , Ventrículos do Coração/enzimologia , Hipertrofia Ventricular Esquerda/enzimologia , Metiltransferases/metabolismo , Miócitos Cardíacos/enzimologia , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Função Ventricular Esquerda , Adenosina/metabolismo , Animais , Células Cultivadas , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Ventrículos do Coração/patologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Metilação , Metiltransferases/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/patologia , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/metabolismo , Poli(ADP-Ribose) Polimerases/genética , Proteínas Proto-Oncogênicas/genética , Estabilidade de RNA , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , Transdução de Sinais , Remodelação Ventricular
10.
In Vitro Cell Dev Biol Anim ; 56(9): 715-722, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33067659

RESUMO

Myocardial infarction is the leading cause of death worldwide, and cardiomyocyte apoptosis during myocardial infarction and reperfusion is a significant factor of poor prognosis. As important regulatory molecules, biofunctions of circRNAs in the pathogenesis of myocardial infarction remain elusive. To confirm the expression level and biological function of circNFIX in cardiomyocytes upon oxidative stress. Divergent polymerase chain reaction and Sanger sequencing were performed to verify the circular structure. The stability of circNFIX was confirmed by RNase R treatment and actinomycin D assay. In order to simulate oxidative stress during myocardial infarction, H9c2 cells were subjected to hydrogen peroxide and hypoxia stimulation. In vivo, mouse models of myocardial ischemia were established. The biological function of circNFIX in cardiomyocytes was investigated through loss- and gain-of-function assays, and cardiomyocyte apoptosis level was detected by the terminal deoxyribonucleotidyl transferase-mediated TdT-mediated dUTP nick end labeling assay and Western blot. CircNFIX is abundant, conserved, and stable in H9c2 cells. The expression of circNFIX was significantly downregulated in cardiomyocytes subjected to oxidative stress. Enforced CircNFIX promotes H9c2 cells apoptosis induced by hydrogen peroxide, in sharp contrast to circNFIX knockdown. In this study, we found that circNFIX served as a pro-apoptosis factor in cardiomyocyte apoptosis. CircNFIX possesses potential to be the biomarker and therapeutic target in myocardial infarction.

11.
Zhongguo Gu Shang ; 33(3): 209-13, 2020 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-32233245

RESUMO

OBJECTIVE: To observe clinical effects of platelet-rich plasma (PRP) intra-articular and extra-articular injection for patients with knee osteoarthritis (KOA), and analyze its safety and clinical efficacy. METHODS: From January to December 2017, 48 patients with KOA were randomly divided into observation group and control group, 24 cases in each group. The observation group was treated with intra-articular injection of PRP (2 ml) and extra-articular injection of PRP (2 ml), once a week, for three times, including 8 males and 16 females with an average of (58.04±7.87) years old ranging from 43 to 68 years old, the courses of disease ranged from 1 to 8 years with an average of (4.69±1.96) years, the body mass index (BMI) was (24.53±5.26) kg/m 2 . The control group was treated with intra-articular injection of sodium hyaluronate (20 mg), extra-articular injection of analgesic drug (2 ml for one point), once a week, for three times, including 7 males and 17 females with an average of (60.54±8.93) years old ranging from 47 to 72 years old, the courses of disease ranged from 1.5 to 9 years with an average of (5.27±1.68) years, BMI was (23.47±4.62) kg/m 2 . VAS score and Lysholm score before operation and the 1st, 6th month after treatment were compared between two groups. RESULTS: All patients were followed up at least 6 months without occurrence serious adverse reactions or complications. VAS score in observation group and control group before treatment and 1st, 6th month after treatment were 7.35±1.47, 4.15±1.52, 2.26±1.02 and 7.51±1.39, 3.84±1.76, 3.66±1.18, respectively; VAS score in obsevation group was lower than that of control group at 6 months after treatment. Lysholm score in observation group and control group before treatment and 1st, 6th month after treatment were 55.21±5.78, 79.16±7.25, 85.45±6.87 and 54.65± 6.40, 77.58±6.94, 82.34±7.12. There were significant differences in Lysholm score before and after injection between two groups (P<0.05) . There was no significant difference in Lysholm score between two groups at 1 month after treatment (P>0.05), while Lysholm score in observation group was better than that of control group at 6 months after treatment (P<0.05) . CONCLUSION: Intra-articular and extra-articular injection of PRP could relieve pain symptoms and improve function of knee joint with higher safety, although the short-term effect is not significantly different from traditional treatment, its medium-long-term effect is stable. It is a safe and effective method for the treatment of knee osteoarthritis.


Assuntos
Osteoartrite do Joelho , Adulto , Idoso , Feminino , Humanos , Ácido Hialurônico , Injeções Intra-Articulares , Articulação do Joelho , Masculino , Pessoa de Meia-Idade , Plasma Rico em Plaquetas , Resultado do Tratamento
12.
Oncol Lett ; 19(2): 1619-1634, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32002039

RESUMO

As the most common type of cancer in female patients, the morbidity and mortality rates of breast cancer (BC) are high, and its incidence is gradually increasing worldwide. However, the underlying molecular and genetic mechanisms involved in the etiopathogenesis of BC remain unclear. Circular RNAs (circRNAs) are a novel type of non-coding RNAs that have been verified to serve a crucial role in tumorigenesis. However, the majority of functions and mechanisms of circRNAs remain unknown. The present study identified 47 differentially expressed circRNAs in a dataset from Gene Expression Omnibus. Using the cancer-specific circRNA database, the potential microRNA (miRNA) response elements, RNA-binding proteins and open reading frames of the candidate circRNAs were predicted. Combing the predictions of miRNAs and target mRNAs, a competing endogenous RNA network was constructed, which may serve as the theoretical basis for further research. Furthermore, the analyses conducted using Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways indicated that candidate circRNAs may serve a role in transcriptional regulation. Moreover, 20 BC tissue specimens and their paired adjacent normal tissue specimens were used to evaluate the expression levels of the screened circRNAs. Thus, the analyses of the raw microarray data conducted in the present study offer perspectives on the exploration of mechanisms associated with BC tumorigenesis with regard to the circRNA-miRNA-mRNA network.

13.
Aging Dis ; 10(6): 1293-1301, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31788340

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder and one of the leading causes of disability and mortality in the late life with no curative treatment currently. Thus, it is urgently to establish sensitive and non-invasive biomarkers for AD diagnosis, particularly in the early stage. Recently, emerging number of microRNAs (miRNAs) and long-noncoding RNAs (lncRNAs) are considered as effective biomarkers in various diseases as they possess characteristics of stable, resistant to RNAase digestion and many extreme conditions in circulatory fluid. This review highlights recent advances in the identification of the aberrantly expressed miRNAs and lncRNAs in circulatory network for detection of AD. We summarized the abnormal expressed miRNAs in blood and cerebrospinal fluid (CSF), and detailed discussed the functions and molecular mechanism of serum or plasma miRNAs-miR-195, miR-155, miR-34a, miR-9, miR-206, miR-125b and miR-29 in the regulation of AD progression. In addition, we also elaborated the role of circulating lncRNA major including beta-site APP cleaving enzyme 1 (BACE1) and its antisense lncRNA BACE1-AS in AD pathological advancement. In brief, confirming the aberrantly expressed circulating miRNAs and lncRNAs will provide an effective testing tools for treatment of AD in the future.

15.
Nanoscale ; 11(36): 16879-16885, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31482918

RESUMO

microRNAs are a type of evolutionarily conserved small non-coding RNA with a length of 18-25 nucleotides. In recent years, increasing studies have shown that the content of specific miRNAs in the blood changes significantly during the occurrence and development of major diseases such as cardiovascular disease and cancer. Therefore, miRNAs may serve as important new biomarkers that can be used for disease diagnosis in the future. Here, we improved the polyethylene glycol layer on the surface of a traditional silicon sphere to specifically capture miRNAs by means of a full-function microplate detector, at 100 microliters. The detection limit for specific miRNAs per liter of plasma can reach 1 fM, and simultaneous detection of 96 samples can be achieved. Compared with the traditional real-time PCR technology, our detection eliminates the complex steps of miRNA extraction, reverse transcription, amplification, etc. and avoids more human error in the detection process. Using the full-featured microwell detector, we can rapidly detect specific miRNAs in plasma, which can be used in the diagnosis of cardiovascular diseases in the future.


Assuntos
Biomarcadores Tumorais/sangue , Doenças Cardiovasculares/sangue , MicroRNA Circulante/sangue , Neoplasias/sangue , RNA Neoplásico/sangue , Adulto , Humanos , Limite de Detecção , Masculino
16.
Mol Cancer ; 18(1): 123, 2019 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399034

RESUMO

Piwi interacting RNAs (piRNAs) constitute novel small non-coding RNA molecules of approximately 24-31 nucleotides in length that often bind to members of the piwi protein family to play regulatory roles. Recently, emerging evidence suggests that in addition to the mammalian germline, piRNAs are also expressed in a tissue-specific manner in a variety of human tissues and modulate key signaling pathways at the transcriptional or post-transcriptional level. In addition, a growing number of studies have shown that piRNA and PIWI proteins, which are abnormally expressed in various cancers, may serve as novel biomarkers and therapeutic targets for tumor diagnostics and treatment. However, the functions of piRNAs in cancer and their underlying mechanisms remain incompletely understood. In this review, we discuss current findings regarding piRNA biogenetic processes, functions, and emerging roles in cancer, providing new insights regarding the potential applications of piRNAs and piwi proteins in cancer diagnosis and clinical treatment.


Assuntos
Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Animais , Biomarcadores Tumorais , Epigênese Genética , Perfilação da Expressão Gênica , Histonas , Humanos , Modelos Biológicos , Neoplasias/metabolismo , RNA Interferente Pequeno/metabolismo
17.
Food Funct ; 10(7): 3880-3889, 2019 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-31187839

RESUMO

Gut microbiota plays an important role in many metabolic diseases and has been linked to cardiovascular disease, including atherosclerosis. Clinical studies suggest that red yeast rice (RYR) has the potential to reduce blood lipid levels. However, the mechanisms under which RYR regulates atherosclerosis by affecting the composition of the gut microbiome have not been elucidated. In the current study, results showed that treatment with RYR significantly decreased the plaque formation and levels of cholesterol and low-density lipoprotein (LDL) compared with the atherosclerotic model group which were fed with a high-fat diet. In addition, the height of enteral villus in the red Monascus group was increased, indicating that RYR can improve the intestinal barrier function. Further analysis revealed that RYR might attenuate atherosclerosis through inhibiting hydroxy methylglutaryl-CoA reductase and the consequent inflammatory signaling pathways mediated by TLR2 and TLR4. Moreover, the RYR treatment led to significant structural changes on the intestinal microbiota of high-fat diet-fed mice and reduced the relative abundance of Alistipes and Flavonifractor that exhibited positive relationships with the plasma levels of cholesterol and LDL. Collectively, these findings illustrated that RYR could significantly protect against atherosclerosis, which was possibly associated with the alterations in the gut microbiota composition.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/tratamento farmacológico , Produtos Biológicos/farmacologia , Dieta Hiperlipídica/efeitos adversos , Microbioma Gastrointestinal/fisiologia , Inflamação , Animais , Aterosclerose/induzido quimicamente , Aterosclerose/patologia , Colesterol/sangue , DNA Bacteriano , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos , Lipídeos/sangue , Lipoproteínas LDL/sangue , Lipoproteínas LDL/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monascus , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/metabolismo
18.
Circulation ; 139(23): 2668-2684, 2019 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-30832495

RESUMO

BACKGROUND: The adult mammalian cardiomyocytes lose their proliferative capacity, which is responsible for cardiac dysfunction and heart failure following injury. The molecular mechanisms underlying the attenuation of adult cardiomyocyte proliferation remain largely unknown. Because long noncoding RNAs (lncRNAs) have a critical role in the development of cardiovascular problems, we investigated whether lncRNAs have any role in the regulation of cardiomyocyte proliferation and cardiac repair. METHODS: Using bioinformatics and initial analysis, we identified an lncRNA, named CPR (cardiomyocyte proliferation regulator), that has a potential regulatory role in cardiomyocyte proliferation. For in vivo experiments, we generated CPR knockout and cardiac-specific CPR-overexpressing mice. In isolated cardiomyocytes, we used adenovirus for silencing (CPR-small interfering RNA) or overexpressing CPR. To investigate the mechanisms of CPR function in cardiomyocyte proliferation, we performed various analyses including quantitative reverse transcription-polymerase chain reaction, Western blot, histology, cardiac function (by echocardiography), transcriptome analyses (microarray assay), RNA pull-down assay, and chromatin immunoprecipitation assay. RESULTS: CPR level is comparatively higher in the adult heart than in the fetal stage. The silencing of CPR significantly increased cardiomyocyte proliferation in postnatal and adult hearts. Moreover, CPR deletion restored the heart function after myocardial injury, which was evident from increased cardiomyocyte proliferation, improvement of myocardial function, and reduced scar formation. In contrast, the neonatal cardiomyocyte proliferation and cardiac regeneration were remarkably suppressed in CPR-overexpressing mice or adeno-associated virus serotype 9-CPR-overexpressing heart. These results indicate that CPR acts as a negative regulator of cardiomyocyte proliferation and regeneration. Next, we found that CPR targets minichromosome maintenance 3, an initiator of DNA replication and cell cycle progression, to suppress cardiomyocyte proliferation. CPR silenced minichromosome maintenance 3 expression through directly interacting and recruiting DNMT3A to its promoter cysteine-phosphate-guanine sites, as evident from decreased minichromosome maintenance 3 promoter methylation and increased minichromosome maintenance 3 expression in CPR knocked-down cardiomyocytes and CPR knockout mouse heart. These results were confirmed in CPR-overexpressing cardiomyocytes and CPR-overexpressing mouse heart. CONCLUSIONS: Together, our findings identified that CPR is a suppressor of cardiomyocyte proliferation and indicated that lncRNAs take part in the regulation of cardiomyocyte proliferation and cardiac repair. Our study provides an lncRNA-based therapeutic strategy for effective cardiac repair and regeneration.


Assuntos
Proliferação de Células , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/metabolismo , Regeneração , Animais , Animais Recém-Nascidos , Sítios de Ligação , Ciclo Celular , Células Cultivadas , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Componente 3 do Complexo de Manutenção de Minicromossomo/genética , Componente 3 do Complexo de Manutenção de Minicromossomo/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/patologia , Regiões Promotoras Genéticas , RNA Longo não Codificante/genética , Transdução de Sinais
19.
FEBS J ; 286(12): 2261-2272, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30927500

RESUMO

Long non-coding RNAs (lncRNAs) are non-protein coding transcripts containing more than 200 nucleotides. In the past, lncRNAs were considered as 'transcript noise' or 'pseudogenes' and were thus ignored. However, in recent years, lncRNAs have been proven to regulate gene expression at the epigenetic, transcriptional and translational level, and thereby influence cell proliferation, apoptosis, viability, immune response and oxidative stress. Furthermore, increasing evidence points to their involvement in different diseases, including cancer and heart diseases. Recently, lncRNAs were shown to be differentially expressed in ocular tissues and play a significant role in the pathogenesis of ophthalmological disorders such as glaucoma, corneal diseases, cataract, diabetic retinopathy, proliferative vitreoretinopathy and ocular tumors. In this review, we summarize the classification and mechanisms of known lncRNAs, while detailing their biological functions and roles in ocular diseases. Moreover, we provide a concise review of the clinical relevance of lncRNAs as novel, potential therapeutic targets in the treatment of eye diseases.


Assuntos
Oftalmopatias/genética , Terapia de Alvo Molecular , RNA Longo não Codificante/genética , Biomarcadores/metabolismo , Olho/metabolismo , Oftalmopatias/classificação , Oftalmopatias/patologia , Humanos , RNA Longo não Codificante/classificação
20.
Int J Biol Sci ; 15(3): 680-687, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30745854

RESUMO

Reactive oxygen species (ROS) are a class of reactive molecules that have been implicated in a variety of cardiovascular diseases, accompanied by disorder of multiple signaling events. As cardiomyocytes maintain abundant of mitochondria, which supply the major source of endogenous ROS, oxidative damage to mitochondria often drives apoptotic cell death and initiates cardiac pathology. In recent years, non-coding RNAs (ncRNAs) have received much attention to uncover their roles in regulating gene expression during those pathological events in the heart, such as myocardial infarction, cardiac hypertrophy, and heart failure. Emerging evidences have highlighted that different ROS levels in response to diverse cardiac stresses result in differential expression of ncRNAs, subsequently altering the expression of pathogenetic genes. However, the knowledge about the ncRNA-linked ROS regulatory mechanisms in cardiac pathologies is still largely unexplored. In this review, we summarize the connections that exist among ROS, ncRNAs, and cardiac diseases to understand the interactions among the molecular entities underlying cardiac pathological events in the hopes of guiding novel therapies for heart diseases in the future.


Assuntos
Doenças Cardiovasculares/metabolismo , RNA não Traduzido/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doenças Cardiovasculares/genética , Humanos , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , RNA não Traduzido/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
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