RESUMO
Cardiac fibrosis is a common pathological manifestation in multiple cardiovascular diseases and often results in myocardial stiffness and cardiac dysfunctions. LncRNA (long noncoding RNA) participates in a number of pathophysiological processes. However, its role in cardiac fibrosis remains unclear. The purpose of this study was to investigate the role and molecular mechanism of MetBil in regulating cardiac fibrosis. Our data showed that METTL3 binding lncRNA (MetBil) was significantly increased both in fibrotic tissue following myocardial infarction (MI) in mice and in cardiac fibroblasts (CFs) exposed to TGF-ß1 (20 ng/mL) or 20% FBS. Overexpression of MetBil augmented collagen deposition, CF proliferation and activation while silencing MetBil exhibited the opposite effects. Importantly, heterozygous knockout of MetBil alleviated cardiac fibrosis and improved cardiac function after MI. RNA pull-down and RNA-binding protein immunoprecipitation assay showed that METTL3 is a direct downstream target of MetBil; consistently, MetBil and METTL3 were co-localized in both the nucleus and cytoplasm of CFs. Interestingly, MetBil regulated METTL3 expression at protein level, but not mRNA level, in ubiquitin-proteasome pathway. Enforced expression of METTL3 canceled the antifibrotic effects of silencing MetBil reflected by increased collagen production, CF proliferation and activation. Most notably, the m6A-modified fibrosis-regulated genes mediated by METTL3 are profoundly involved in the regulation of MetBil in the cardiac fibrosis following MI. Our study reveals that MetBil as a novel regulator of fibrosis promotes cardiac fibrosis via interacting with METTL3 and regulating the expression of the methylated fibrosis-associated genes, providing a new intervening target for fibrosis-associated cardiac diseases.
Assuntos
Cardiopatias , Infarto do Miocárdio , RNA Longo não Codificante , Camundongos , Animais , RNA Longo não Codificante/genética , Infarto do Miocárdio/metabolismo , Fibrose , Metiltransferases/genética , Metiltransferases/metabolismo , Colágeno/genética , Colágeno/metabolismoRESUMO
BACKGROUND: Ku70 participates in several pathological processes through mediating repair of DNA double-strand breaks. Our previous study has identified a highly conserved long noncoding RNA cardiac ischemia reperfusion associated Ku70 interacting lncRNA (CIRKIL) that was upregulated in myocardial infarction. The study aims to investigate whether CIRKIL regulates myocardial ischemia/reperfusion (I/R) through binding to Ku70. METHODS: CIRKIL transgenic and knockout mice were subjected to 45-minute ischemia and 24-hour reperfusion to establish myocardial I/R model. RNA pull-down and RNA immunoprecipitation assay were used to detect the interaction between CIRKIL and Ku70. RESULTS: The expression of CIRKIL was increased in I/R myocardium and H2O2-treated cardiomyocytes. Overexpression of CIRKIL increased the expression of γH2A.X, a specific marker of DNA double-strand breaks and aggravated cardiomyocyte apoptosis, whereas knockdown of CIRKIL produced the opposite changes. Transgenic overexpression of CIRKIL aggravated cardiac dysfunction, enlarged infarct area, and worsened cardiomyocyte damage in I/R mice. Knockout of CIRKIL alleviated myocardial I/R injury. Mechanistically, CIRKIL directly bound to Ku70 to subsequently decrease nuclear translocation of Ku70 and impair DNA double-strand breaks repair. Concurrent overexpression of Ku70 mitigated CIRKIL overexpression-induced myocardial I/R injury. Furthermore, knockdown of human CIRKIL significantly suppressed cell damage induced by H2O2 in adult human ventricular cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes. CONCLUSIONS: CIRKIL is a detrimental factor in I/R injury acting via regulating nuclear translocation of Ku70 and DNA double-strand breaks repair. Thus, CIRKIL might be considered as a novel molecular target for the treatment of cardiac conditions associated with I/R injury.
Assuntos
Doença da Artéria Coronariana , Células-Tronco Pluripotentes Induzidas , Infarto do Miocárdio , Isquemia Miocárdica , Traumatismo por Reperfusão Miocárdica , RNA Longo não Codificante , Animais , Apoptose , Doença da Artéria Coronariana/metabolismo , DNA/metabolismo , Humanos , Peróxido de Hidrogênio/toxicidade , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Camundongos Knockout , Infarto do Miocárdio/metabolismo , Isquemia Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , ReperfusãoRESUMO
Myocardial ischemia-reperfusion (I/R) injury is a pathological process characterized by cardiomyocyte apoptosis, which leads to cardiac dysfunction. Increasing evidence shows that abnormal expression of long noncoding RNAs (lncRNAs) plays a crucial role in cardiovascular diseases. In this study we investigated the role of lncRNAs in myocardial I/R injury. Myocardial I/R injury was induced in mice by ligating left anterior descending coronary artery for 45 min followed by reperfusion for 24 h. We showed that lncRNA KnowTID_00006395, termed lncRNA-6395 was significantly upregulated in the infarct area of mouse hearts following I/R injury as well as in H2O2-treated neonatal mouse ventricular cardiomyocytes (NMVCs). Overexpression of lncRNA-6395 led to cell apoptosis and the expression change of apoptosis-related proteins in NMVCs, whereas knockdown of lncRNA-6395 attenuated H2O2-induced cell apoptosis. LncRNA-6395 knockout mice (lncRNA-6395+/-) displayed improved cardiac function, decreased plasma LDH activity and infarct size following I/R injury. We demonstrated that lncRNA-6395 directly bound to p53, and increased the abundance of p53 protein through inhibiting ubiquitination-mediated p53 degradation and thereby facilitated p53 translocation to the nucleus. More importantly, overexpression of p53 canceled the inhibitory effects of lncRNA-6395 knockdown on cardiomyocyte apoptosis, whereas knockdown of p53 counteracted the apoptotic effects of lncRNA-6395 in cardiomyocytes. Taken together, lncRNA-6395 as an endogenous pro-apoptotic factor, regulates cardiomyocyte apoptosis and myocardial I/R injury by inhibiting degradation and promoting sub-cellular translocation of p53.
Assuntos
Traumatismo por Reperfusão Miocárdica , RNA Longo não Codificante , Animais , Apoptose , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/farmacologia , Peróxido de Hidrogênio/farmacologia , Infarto/patologia , Camundongos , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Blood-contact devices are prone to inflammation, endothelial dysfunction, coagulation, and the uncontrolled release of metal ions during implantation and service. Therefore, it is essential to make these multifunctional. Herein, a superhydrophobic DE@ZnS-ZnO@SA film (composed of dabigatran ester, zinc sulfite, zinc oxide, and stearic acid, respectively) is produced. The prepared film has non-adhesion and antibacterial properties, superior mechanical stability, durability, corrosion resistance, and is self-cleaning and blood-repellent. The results of the hemolysis, cytotoxicity, and other anticoagulant experiments revealed that the film had good blood compatibility, no cytotoxicity, and excellent anticoagulant properties. The film displays anticoagulant properties even after being immersed in Phosphate-Buffered Saline (PBS) for 7 days. Furthermore, the film can spontaneously release H2S gas for 90 h after soaking in an acidic environment (pH = 6) for 90 h. This property improves the acidic microenvironment of the lesion and promotes the proliferation of endothelial cells by using H2S gas. In addition, the film can inhibit the uncontrollable release of Zn2+ ions, avoiding its toxicity even when immersed in an acid environment for 35 days. This time-sequential functionalized surface has the potential to typify the future of blood-contacting scaffolds for long-lasting use.
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Compostos de Zinco , Óxido de Zinco , Óxido de Zinco/química , Compostos de Zinco/química , Humanos , Propriedades de Superfície , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Sulfetos/química , Hemólise/efeitos dos fármacos , Antibacterianos/química , Antibacterianos/farmacologia , Animais , Células Endoteliais da Veia Umbilical HumanaRESUMO
Non-small cell lung cancer (NSCLC) is a highly lethal disease with a complex and heterogeneous tumor microenvironment. Currently, common animal models based on subcutaneous inoculation of cancer cell suspensions do not recapitulate the tumor microenvironment in NSCLC. Herein we describe a murine orthotopic lung cancer xenograft model that employs the intrapulmonary inoculation of three-dimensional multicellular spheroids (MCS). Specifically, fluorescent human NSCLC cells (A549-iRFP) were cultured in low-attachment 96-well microplates with collagen for 3 weeks to form MCS, which were then inoculated intercostally into the left lung of athymic nude mice to establish the orthotopic lung cancer model. Compared with the original A549 cell line, MCS of the A549-iRFP cell line responded similarly to anticancer drugs. The long-wavelength fluorescent signal of the A549-iRFP cells correlated strongly with common markers of cancer cell growth, including spheroid volume, cell viability, and cellular protein level, thus allowing dynamic monitoring of the cancer growth in vivo by fluorescent imaging. After inoculation into mice, the A549-iRFP MCS xenograft reliably progressed through phases closely resembling the clinical stages of NSCLC, including the expansion of the primary tumor, the emergence of neighboring secondary tumors, and the metastases of cancer cells to the contralateral right lung and remote organs. Moreover, the model responded to the benchmark antilung cancer drug, cisplatin with the anticipated toxicity and slower cancer progression. Therefore, this murine orthotopic xenograft model of NSCLC would serve as a platform to recapitulate the disease's progression and facilitate the development of potential anticancer drugs.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Camundongos Nus , Animais , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/tratamento farmacológico , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Progressão da Doença , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/patologia , Modelos Animais de Doenças , Células A549 , Transplante de NeoplasiasRESUMO
Climate warming poses a serious threat to soil biodiversity and crop yield. Application of organic fertilizer has been extensively practiced to improve soil health and crop productivity. However, information is limited about the effects of organic fertilizer on microbial communities and diversity (richness) under warming. Thus, to investigate the interactive effects of temperature (ambient temperature and warming) and fertilizer (chemical fertilizer and partial substitution of chemical fertilizer with organic fertilizer) on microbial properties and wheat yield, a two-factorial pot experiment was conducted using soils with high and low fertility The results showed that warming and organic fertilizer had minor effects on bacterial Shannon and Simpson indexes. Due to concomitant reductions in soil moisture, warming decreased the average Chao index by 5.4 % and Ace index by 3.8 % for soils with high and low fertility (P < 0.05). High-throughput sequence presented that dominated genus was Bacillus with spore-forming ability. Under warming and drying conditions, microbes with adaptive traits (spore-forming ability) would outcompete the other microbes, and decrease microbial Chao and Ace index (richness). However, organic fertilizer counteracted the adverse effects of warming on microbial richness attributed to positive interaction between temperature and fertilizer on soil nutrients and organic carbon. The strong relationships between bacterial richness and wheat yield, as well as soil nutrients, highlighted the importance of soil biodiversity in improving soil nutrients and crop productivity. Partial substitution of chemical fertilizer with organic fertilizer significantly increased wheat yield by 27.1 % and 14.9 % under ambient temperature and by 28.0 % and 19.6 % under warming for soils with high and low fertility, respectively. Overall, this study provided the possibility to increase bacterial richness related to nutrient turnover and crop production by organic fertilizer application with reduced chemical fertilizer, especially under climate warming.
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Fertilizantes , Microbiologia do Solo , Solo , Triticum , Triticum/microbiologia , Solo/química , Biodiversidade , Aquecimento Global , Microbiota , Bactérias , Agricultura/métodosRESUMO
Fluoride ions (F-) are one of the essential trace elements for the human body and are widely existed in nature. In this study, we present a novel fluorescent probe (YF-SZ-F) designed and synthesized for the specific detection of F-. The probe exhibits high sensitivity, excellent selectivity, and low cytotoxicity, making it a promising tool for biomedical applications. Imaging experiments conducted on zebrafish and Arabidopsis roots demonstrate the probe's remarkable cellular permeability and biocompatibility, laying a solid foundation for its potential biomedical utility. Furthermore, the probe holds potential for practical applications in environmental monitoring and public health through its capability to detect fluoride ions in water samples and via mobile phone software. This multifaceted functionality underscores the broad applicability and significance of the fluorescent probe, not only in scientific research but also in real-world scenarios, contributing to the development of more convenient and precise methods for fluoride detection.
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Apolipoprotein E (apoE) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Microglia exhibit a substantial upregulation of apoE in AD-associated circumstances, despite astrocytes being the primary source of apoE expression and secretion in the brain. Although the role of astrocytic apoE in the brain has been extensively investigated, it remains unclear that whether and how apoE particles generated from astrocytes and microglia differ in biological characteristic and function. Here, we demonstrate the differences in size between apoE particles generated from microglia and astrocytes. Microglial apoE particles impair neurite growth and synapses, and promote neuronal senescence, whereas depletion of GPNMB (glycoprotein non-metastatic melanoma protein B) in microglial apoE particles mitigated these deleterious effects. In addition, human APOE4-expressing microglia are more neurotoxic than APOE3-bearing microglia. For the first time, these results offer concrete evidence that apoE particles produced by microglia are involved in neuronal senescence and toxicity.
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There is an urgent need to develop a series of multifunctional materials with good biocompatibility, high mechanical strength, hemostatic properties, antiadhesion, and anti-infection for applications in wound care. However, successfully developing multifunctional materials is challenging. In this study, two superhydrophobic composite coatings with good biocompatibility, high mechanical strength, strong antifouling and blood repellency, fast hemostasis, and good antibacterial activity are prepared on cotton fabric surface by simple, green, and low-cost one-step dip-coating technology. The results discussed in the manuscript reveals that the two superhydrophobic composite coatings can maintain good mechanical stability, strong water repellency, and durability under various types of mechanical damage, high-temperature treatment, and long-term strong light irradiation. The coatings also exhibit good repellency to various solid pollutants, highly viscous liquid pollutants, and blood. In vitro and in vivo hemostatic experiments show that both composite coatings have good hemostatic and anticlot adhesion properties. More importantly, this superhydrophobic coating prevents bacterial adhesion and growth and released Cu2+ and Zn2+ ions and chitosan to achieve bactericidal properties, thereby protecting injured skin from bacterial infection. The two superhydrophobic coatings enhance the antifouling, antiadhesion, hemostatic, and antibacterial functions of blood-repellent dressings and therefore have broad application prospects in medical and textile fields.
Assuntos
Quitosana , Poluentes Ambientais , Hemostáticos , Interações Hidrofóbicas e Hidrofílicas , Antibacterianos/farmacologia , Antibacterianos/química , ZincoRESUMO
Naked medical devices are often damaged by blood, bacteria, and other extreme environmental conditions (heat, humidity, acid, alkali, salts, and others), causing device failure and increasing difficulty for the operator. They can also cause inflammation and coagulation resulting in severe complications and even death. In this work, the superhydrophobic ZnO/copper-zinc metal-organic frameworks@stearic acid (ZnO/Cu-ZnMOFs@SA) composite coatings with hierarchical micro/nanostructures were fabricated on Zn substrates via a one-step hydrothermal method. The effects of hierarchical micro/nanostructures on surface wettability, physicochemical stability, and biological properties have been studied in this manuscript. The structure not only provided the coatings with robust waterproofing, abrasive resistance, durability, and thermal and light irradiation stability but also successfully recovered their superhydrophobicity by remodifying the surface with SA, showing excellent repeatability. In addition, the coating demonstrates excellent corrosion resistance and self-cleaning ability and rejects various solid and liquid contaminants. The superhydrophobic ZnO/Cu-ZnMOFs@SA composite coatings also exhibited excellent antibacterial and thrombosis resistance. The findings indicated that the superhydrophobic composite coatings have a strong potential for application in medical instruments for exhibiting multifunctional properties in various extreme environments.
Assuntos
Nanoestruturas , Óxido de Zinco , Óxido de Zinco/farmacologia , Óxido de Zinco/química , Nanoestruturas/química , Molhabilidade , Antibacterianos/farmacologia , Antibacterianos/química , Coagulação SanguíneaRESUMO
The mercury ion (Hg2+) has hindered society to some extent due to its high biological toxicity, and a rapid method for Hg2+ detection is urgently needed. In the present work, two fluorescent probes, YF-Hg and YF-Cl-Hg, were developed. YF-Cl-Hg was produced by introducing an electron-withdrawing substituent (-Cl) into the structure of YF-Hg. The probe YF-Cl-Hg possesses a larger Stokes shift and a more pronounced UV-vis absorption redshift compared to YF-Hg in a pH = 7.4 environment. The reasons for the superior spectral performance of YF-Cl-Hg over YF-Hg were explored by density functional theory (DFT) calculations and UV-vis absorption spectroscopy. Furthermore, the good biocompatibility suggests that YF-Cl-Hg possesses the potential to be a tool for Hg2+ detection in cells.
Assuntos
Corantes Fluorescentes , Mercúrio , Corantes Fluorescentes/química , Espectrometria de Fluorescência/métodos , Diagnóstico por ImagemRESUMO
Background: Since the application of Immune checkpoint inhibitors (ICI), the clinical outcome for metastatic cancer has been greatly improved. Nevertheless, treatment response varies in patients, making it urgent to identify patients who will receive clinical benefits after ICI therapy. Adipose body composition has proved to be associated with tumor response. In this systematic review, we aimed to summarize the current evidence on imaging adipose biomarkers that predict clinical outcomes in patients treated with ICI in various cancer types. Methods: Embase and PubMed were searched from database inception to 1st February 2023. Articles included investigated the association between imaging-based adipose biomarkers and the clinical outcomes of patients treated with ICI. The methodological quality of included studies was evaluated through Newcastle- Ottawa Quality Assessment Scale and Radiomics Quality Score tools. Results: Totally, 22 studies including 2256 patients were selected. Non-small cell lung cancer (NSCLC) had the most articles (6 studies), followed by melanoma (5 studies), renal cell carcinoma (RCC) (3 studies), urothelial carcinoma (UC) (2 studies), head and neck squamous cell carcinoma (HNSCC) (1 study), gastric cancer (1 study) and liver cancer (1 study). The remaining 3 studies investigated metastatic solid tumors including various types of cancers. Adipose biomarkers can be summarized into 5 categories, including total fat, visceral fat, subcutaneous fat, intramuscular fat and others, which exerted diverse correlations with patients' prognosis after being treated with ICI in different cancers. Most biomarkers of body fat were positively associated with survival benefits. Nevertheless, more total fat was predictable of worse outcomes in NSCLC, while inter-muscular fat was associated with poor clinical benefits in UC. Conclusion: There is relatively well-supported evidence for imaging-based adipose biomarkers to predict the clinical outcome of ICI. In general, most of the studies show that adipose tissue is positively correlated with clinical outcomes. This review summarizes the significant biomarkers proven by researches for each cancer type. Further validation and large independent prospective cohorts are needed in the future. The protocol of this systematic review has been registered at the International Prospective Register of Systematic Reviews (http://www.crd.york.ac.uk/PROSPERO, registration no: CRD42023401986).
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Hg2+ in the environment endangers human health, and a convenient monitoring method is needed for the detection of Hg2+. In this study, we constructed a dual colorimetric near-infrared fluorescent probe (E)-2-(3-(3-(1,3-dithian-2-yl)-4-hydroxystyryl)-5,5-dimethylcyclohex-2-en-1-ylidene)malononitrile (YF-Hg), based on the malononitrile isophorone. YF-Hg can detect Hg2+ rapidly and sensitively, with fluorescence emission in the near-infrared region (659 nm) with an obvious color change from violet to red in the visible light range. In addition, the low toxicity and large Stokes shift (191 nm) of YF-Hg also suggest that it is a potential tool for live-cell fluorescence imaging.
Assuntos
Colorimetria , Mercúrio , Humanos , Colorimetria/métodos , Corantes Fluorescentes , Células HeLa , Imagem ÓpticaRESUMO
Speckle-type pox virus and zinc finger (POZ) protein (SPOP), a substrate recognition adaptor of cullin-3 (CUL3)/RING-type E3 ligase complex, is investigated for its role in cardiac fibrosis in our study. Cardiac fibroblasts (CFs) activation was achieved with TGF-ß1 (20 ng/mL) and MI mouse model was established by ligation of the left anterior descending coronary, and lentivirus was employed to mediate interference of SPOP expression. SPOP was increased both in fibrotic post-MI mouse hearts and TGF-ß1-treated CFs. The gain-of-function of SPOP promoted myofibroblast transformation in CFs, and exacerbated cardiac fibrosis and cardiac dysfunction in MI mice, while the loss-of-function of SPOP exhibited the opposite effects. Mechanistically, SPOP bound to the receptor of activated protein C kinase 1 (RACK1) and induced its ubiquitination and degradation by recognizing Ser/Thr-rich motifs on RACK1, leading to Smad3-mediated activation of CFs. Forced RACK1 expression canceled the effects of SPOP on cardiac fibrosis. The study reveals therapeutic targets for fibrosis-related cardiac diseases.
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Infarto do Miocárdio , Fator de Crescimento Transformador beta1 , Animais , Camundongos , Fibrose , Infarto do Miocárdio/complicações , Infarto do Miocárdio/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Receptores de Quinase C Ativada , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologiaRESUMO
The anticoagulation and antibacterial functions of implant and interventional catheters during indwelling will determine their success or failure. Here, an amino-containing copper-based metal-organic framework (Cu-MOF) coating was prepared on the thermoplastic polyurethane substrate (TPU) surface by spin coating for anti-thrombotic and anti-infection effects. The adhesion properties of the polyurethane prepolymer coating (PC) enhanced the binding force of Cu-MOF particles and TPU surface and improved stability. Due to the coordination affinity of Cu2+ with nitric oxide (NO) and the NO loading capacity of the amino group, it showed that a large amount of NO was loaded in the coating. Meanwhile, the coordinated Cu2+ in the coating also catalyzed endogenous NO donors to generate NO, which prolonged the NO release for up to 30 days. The results of antibacterial experiments showed that the NO released from the coating had good antibacterial effects on both E. coli and S. epidermidis. An obvious antibacterial ring can be seen and the antibacterial rate was higher than 96%. It also showed inhibiting platelet adhesion and activation, prolonged in vitro clotting time and inhibited thrombus formation. In summary, for the first time, NO release from the coating was realized by the combined ways of NO donor and catalytic endogenous NO donor. It can not only meet the high NO release rate required for early anticoagulation and antibacterial of the catheter but also maintain normal anticoagulation requirements in the later period.
Assuntos
Escherichia coli , Óxido Nítrico , Óxido Nítrico/química , Poliuretanos/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Anticoagulantes/farmacologia , Cobre/farmacologia , Cobre/químicaRESUMO
Diabetic cardiomyopathy (DCM) is a common complication in diabetic patients. The molecular mechanisms of DCM remain to be fully elucidated. The intronic long noncoding RNA of DACH1 (lncDACH1) has been demonstrated to be closely associated with heart failure and cardiac regeneration. In this study, we investigated the role of lncDACH1 in DCM and the underlying molecular mechanisms. The expression of lncDACH1 was increased in DCM hearts and in high glucose-treated cardiomyocytes. Knockout of lncDACH1 reduced mitochondrial oxidative stress, cell apoptosis, cardiac fibrosis and hypertrophy, and improved cardiac function in DCM mice. Overexpression of lncDACH1 exacerbated mitochondria-derived reactive oxygen species (ROS) level and apoptosis, decreased activity of manganese superoxide dismutase (Mn-SOD); while silencing of lncDACH1 attenuated ROS production, mitochondrial dysfunction, cell apoptosis, and increased the activity of Mn-SOD in cardiomyocytes treated with high glucose. LncDACH1 directly bound to sirtuin3 (SIRT3) and facilitated its degradation by ubiquitination, therefore promoting mitochondrial oxidative injury and cell apoptosis in mouse hearts. In addition, SIRT3 silencing abrogated the protective effects of lncDACH1 deficiency in cardiomyocytes. In summary, lncDACH1 aggravates DCM by promoting mitochondrial oxidative stress and cell apoptosis via increasing ubiquitination-mediated SIRT3 degradation in mouse hearts. Inhibition of lncDACH1 represents a novel therapeutic strategy for the intervention of diabetic cardiomyopathy.
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Diabetes Mellitus , Cardiomiopatias Diabéticas , RNA Longo não Codificante , Sirtuína 3 , Animais , Apoptose/genética , Diabetes Mellitus/metabolismo , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/metabolismo , Glucose/farmacologia , Humanos , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , RNA Longo não Codificante/genética , Espécies Reativas de Oxigênio/metabolismo , Sirtuína 3/genética , Sirtuína 3/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismoRESUMO
MicroRNAs (miRNAs) act as important post-transcriptional regulators of gene expression by targeting the 3'-untranslated region of their target genes. Altered expression of miR-16 is reported in human ulcerative colitis (UC), but its role in the development of the disease remains unclear. Adenosine through adenosine A2a receptor (A2aAR) could inhibit nuclear factor-kappaB (NF-κB) signaling pathway in inflammation. Here we identified overexpression of miR-16 and down-regulation of A2aAR in the colonic mucosa of active UC patients. We demonstrated that miR-16 negatively regulated the expression of the A2aAR at the post-transcriptional level. Furthermore, transfection of miR-16 mimics promoted nuclear translocation of NF-κB p65 protein and expression of pro-inflammatory cytokines, IFN-γ and IL-8 in colonic epithelial cells. Treatment with miR-16 inhibitor could reverse these effects in cells. The A2aAR-mediated effects of miR-16 on the activation of the NF-κB signaling pathway were confirmed by the A2aAR knockdown assay. Our results suggest that miR-16 regulated the immune and inflammatory responses, at least in part, by suppressing the expression of the A2aAR to control the activation of the NF-κB signaling pathway.