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1.
Cells ; 10(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34360007

RESUMO

Since mitochondria are suggested to be important regulators in maintaining cartilage homeostasis, turnover of mitochondria through mitochondrial biogenesis and mitochondrial degradation may play an important role in the pathogenesis of osteoarthritis (OA). Here, we found that mitochondrial dysfunction is closely associated with OA pathogenesis and identified the peroxisome proliferator-activated receptor-gamma co-activator 1-alpha (PGC1α) as a potent regulator. The expression level of PGC1α was significantly decreased under OA conditions, and knockdown of PGC1α dramatically elevated the cartilage degradation by upregulating cartilage degrading enzymes and apoptotic cell death. Interestingly, the knockdown of PGC1α activated the parkin RBR E3 ubiquitin protein ligase (PRKN)-independent selective mitochondria autophagy (mitophagy) pathway through the upregulation of BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (BNIP3). The overexpression of BNIP3 stimulated mitophagy and cartilage degradation by upregulating cartilage-degrading enzymes and chondrocyte death. We identified microRNA (miR)-126-5p as an upstream regulator for PGC1α and confirmed the direct binding between miR-126-5p and 3' untranslated region (UTR) of PGC1α. An in vivo OA mouse model induced by the destabilization of medial meniscus (DMM) surgery, and the delivery of antago-miR-126 via intra-articular injection significantly decreased cartilage degradation. In sum, the loss of PGC1α in chondrocytes due to upregulation of miR-126-5p during OA pathogenesis resulted in the activation of PRKN-independent mitophagy through the upregulation of BNIP3 and stimulated cartilage degradation and apoptotic death of chondrocytes. Therefore, the regulation of PGC1α:BNIP3 mitophagy axis could be of therapeutic benefit to cartilage-degrading diseases.


Assuntos
Cartilagem Articular/metabolismo , Proteínas de Membrana/genética , MicroRNAs/genética , Proteínas Mitocondriais/genética , Mitofagia/genética , Osteoartrite/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Animais , Antagomirs/genética , Antagomirs/metabolismo , Artroplastia do Joelho/métodos , Sequência de Bases , Cartilagem Articular/patologia , Condrócitos/metabolismo , Condrócitos/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Proteínas de Membrana/metabolismo , Meniscos Tibiais/metabolismo , Meniscos Tibiais/patologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas Mitocondriais/metabolismo , Osteoartrite/metabolismo , Osteoartrite/patologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/antagonistas & inibidores , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
2.
Cells ; 10(8)2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34440834

RESUMO

Novel target therapy is on the spotlight for effective cancer therapy. Hence, in the present study, the underlying apoptotic mechanism of Morusin was explored in association with miR193a-5p mediated ZNF746/c-Myc signaling axis in colorectal cancer cells (CRCs). Herein, Morusin reduced the viability and the number of colonies in HCT116 and SW480 CRCs. Additionally, Morusin increased sub-G1 population, cleavages of poly (ADP-ribose) polymerase (PARP) and caspase-3 and inhibited the expression of zinc finger protein 746 (ZNF746) and c-Myc in HCT116 and SW480 cells. Conversely, overexpression of ZNF746 suppressed the ability of Morusin to abrogate the expression of c-Myc in HCT116 cells, as ZNF746 enhanced the stability of c-Myc via their direct binding through nuclear colocalization in HCT116 cells by immunofluorescence and immunoprecipitation. Notably, Morusin upregulated miR193a-5p as a tumor suppressor, while miR193a-5p inhibitor masked the ability of Morusin to reduce the expression of ZNF746, c-Myc, and pro-PARP in HCT116 cells. To our knowledge, these findings provide the novel insight on miR193a-5p mediated inhibition of ZNF746/c-Myc signaling in Morusin induced apoptosis in CRCs.


Assuntos
Apoptose/efeitos dos fármacos , Flavonoides/farmacologia , MicroRNAs/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Repressoras/metabolismo , Regiões 3' não Traduzidas , Antagomirs/metabolismo , Sequência de Bases , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Regulação para Baixo/efeitos dos fármacos , Flavonoides/química , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Ligação Proteica , Estabilidade Proteica , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Repressoras/química , Proteínas Repressoras/genética , Alinhamento de Sequência , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
3.
Cells ; 10(8)2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34440835

RESUMO

Brain homeostasis needs continuous exchange of intercellular information among neurons, glial cells, and immune cells, namely microglial cells. Extracellular vesicles (EVs) are active players of this process. All the cells of the body, including the brain, release at least two subtypes of EVs, the medium/large EVs (m/lEVs) and small EVs (sEVs). sEVs released by microglia play an important role in brain patrolling in physio-pathological processes. One of the most common and malignant forms of brain cancer is glioblastoma. Altered intercellular communications constitute a base for the onset and the development of the disease. In this work, we used microglia-derived sEVs to assay their effects in vitro on murine glioma cells and in vivo in a glioma model on C57BL6/N mice. Our findings indicated that sEVs carry messages to cancer cells that modify glioma cell metabolism, reducing lactate, nitric oxide (NO), and glutamate (Glu) release. sEVs affect Glu homeostasis, increasing the expression of Glu transporter Glt-1 on astrocytes. We demonstrated that these effects are mediated by miR-124 contained in microglia-released sEVs. The in vivo benefit of microglia-derived sEVs results in a significantly reduced tumor mass and an increased survival of glioma-bearing mice, depending on miR-124.


Assuntos
Vesículas Extracelulares/metabolismo , Ácido Glutâmico/metabolismo , MicroRNAs/metabolismo , Microglia/metabolismo , Animais , Antagomirs/metabolismo , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Proliferação de Células , Células Cultivadas , Transportador 2 de Aminoácido Excitatório/genética , Transportador 2 de Aminoácido Excitatório/metabolismo , Vesículas Extracelulares/transplante , Glioma/mortalidade , Glioma/patologia , Glioma/terapia , Interferon gama/farmacologia , Estimativa de Kaplan-Meier , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Microglia/citologia , Microglia/efeitos dos fármacos , Óxido Nítrico/metabolismo , Regulação para Cima
4.
Cell Prolif ; 54(7): e13074, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34101281

RESUMO

OBJECTIVES: Pulp regeneration brings big challenges for clinicians, and vascularization is considered as its determining factor. We previously accomplished pulp regeneration with autologous stem cells from deciduous teeth (SHED) aggregates implantation in teenager patients, however, the underlying mechanism needs to be clarified for regenerating pulp in adults. Serving as an important effector of mesenchymal stem cells (MSCs), exosomes have been reported to promote angiogenesis and tissue regeneration effectively. Here, we aimed to investigate the role of SHED aggregate-derived exosomes (SA-Exo) in the angiogenesis of pulp regeneration. MATERIALS AND METHODS: We extracted exosomes from SHED aggregates and utilized them in the pulp regeneration animal model. The pro-angiogenetic effects of SA-Exo on SHED and human umbilical vein endothelial cells (HUVECs) were evaluated. The related mechanisms were further investigated. RESULTS: We firstly found that SA-Exo significantly improved pulp tissue regeneration and angiogenesis in vivo. Next, we found that SA-Exo promoted SHED endothelial differentiation and enhanced the angiogenic ability of HUVECs, as indicated by the in vitro tube formation assay. Mechanistically, miR-26a, which is enriched in SA-Exo, improved angiogenesis both in SHED and HUVECs via regulating TGF-ß/SMAD2/3 signalling. CONCLUSIONS: In summary, these data reveal that SA-Exo shuttled miR-26a promotes angiogenesis via TGF-ß/SMAD2/3 signalling contributing to SHED aggregate-based pulp tissue regeneration. These novel insights into SA-Exo may facilitate the development of new strategies for pulp regeneration.


Assuntos
Polpa Dentária/fisiologia , Exossomos/metabolismo , MicroRNAs/metabolismo , Neovascularização Fisiológica , Transdução de Sinais , Compostos de Anilina/farmacologia , Antagomirs/metabolismo , Compostos de Benzilideno/farmacologia , Diferenciação Celular/efeitos dos fármacos , Exossomos/transplante , Células Endoteliais da Veia Umbilical Humana , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Neovascularização Fisiológica/efeitos dos fármacos , Regeneração/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Dente Decíduo/citologia , Fator de Crescimento Transformador beta/metabolismo
5.
Int J Nanomedicine ; 16: 3565-3578, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34079249

RESUMO

Background: Renal fibrosis is a chronic and progressive process affecting kidneys in chronic kidney disease (CKD). Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been shown to alleviate renal fibrosis and injury, but the mechanism of MSCs-Exo-induced renal protection remains unknown. Methods: In this study, MSCs were transfected with let-7i-5p antagomir (anti-let-7i-5p), and then exosomes were isolated from the transfected MSCs to deliver anti-let-7i-5p oligonucleotides to inhibit the level of let-7i-5p in kidney tubular epithelial cells (NRK-52E). Results: In both NRK-52E cells stimulated by TGF-ß1 and the mouse kidneys after unilateral ureteral obstruction (UUO), we demonstrated increased level of let-7i-5p. In addition, MSCs-Exo can deliver anti-let-7i-5p to reduce the level of let-7i-5p in NRK-52E cells and increase the expression of its target gene TSC1. Moreover, exosomal anti-let-7i-5p reduced extracellular matrix (ECM) deposition and attenuated epithelial-mesenchymal transition (EMT) process in transforming growth factor beta 1 (TGF-ß1)-stimulated NRK-52E cells and in the kidneys of UUO-treated mice. Meanwhile, mice received exosomal anti-let-7i-5p displayed reduced renal fibrosis and improved kidney function when challenged with UUO. Furthermore, exosomal anti-let-7i-5p promoted the activation the tuberous sclerosis complex subunit 1/mammalian target of rapamycin (TSC1/mTOR) signaling pathway in vivo and in vitro. Conclusion: In conclusion, exosomal anti-let-7i-5p from MSCs exerts anti-fibrotic effects in TGF-ß1-induced fibrogenic responses in NRK52E cells in vitro as well as in UUO-induced renal fibrosis model in vivo. These results provided a novel perspective on improving renal fibrosis by MSCs-Exo.


Assuntos
Antagomirs/metabolismo , Exossomos/metabolismo , Rim/patologia , Células-Tronco Mesenquimais/citologia , MicroRNAs/genética , Animais , Transição Epitelial-Mesenquimal , Matriz Extracelular/metabolismo , Fibrose , Humanos , Masculino , Camundongos , Transdução de Sinais
6.
Acta Biochim Pol ; 68(2): 201-206, 2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-33966370

RESUMO

Sepsis is a systemic inflammatory response syndrome caused by various pathogenic microorganisms or toxins. Lung damage is one of the causes of death in patients with sepsis. This study aimed to investigate the role of miR-19a-3p and its regulation mechanism in sepsis-induced lung injury. MH-S cells were treated with lipopolysaccharide (LPS) to establish sepsis-induced lung injury cell model. C57BL/6 mice were injected with miR-19a-3p antagomiR and LPS to construct animal model. LPS-treated and control cells were transfected with miR-19a-3p mimic, miR-19a-3p inhibitor or USP13 expression vector . The expression levels of miR-19a-3p and USP13 were examined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. The concentration of inflammatory cytokines was measured with enzyme-linked immunosorbent assay (ELISA). The relationship of miR-19a-3p and USP13 was validated using dual-luciferase reporter assay. The lung damage was assessed with hematoxylin-eosin staining (HE). The results showed that LPS treatment increased the concentration of TNF-α, IL-6 and IL-1ß in MH-S cells. In LPS treated MH-S cells, the level of miR-19a-3p gradually increased over time. Both miR-19a-3p knockdown and USP13 overexpression in MH-S cells inhibited the LPS-induced production of TNF-α, IL-6 and IL-1ß. Moreover, miR-19a-3p negatively regulated the expression of USP13 in MH-S cells. Furthermore, miR-19a-3p inhibitor suppressed lung damage in sepsis model mice. In conclusion, miR-19a-3p knockdown could alleviate sepsis-induced lung injury through enhancing USP13 expression.


Assuntos
Lesão Pulmonar/metabolismo , MicroRNAs/metabolismo , Sepse/metabolismo , Proteases Específicas de Ubiquitina/metabolismo , Animais , Antagomirs/genética , Antagomirs/metabolismo , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes/métodos , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/efeitos adversos , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Sepse/complicações , Sepse/patologia , Fator de Necrose Tumoral alfa/metabolismo
7.
PLoS One ; 16(3): e0249146, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33760887

RESUMO

Vascular remodeling and contraction contribute to the development of hypertension. We investigated the role of miR-212-5p and its downstream target in vascular smooth muscle cell (VSMC) proliferation, migration, and contraction. MicroRNA microarray and PCR analyses showed that miR-212-5p expression was increased with angiotensin II treatment in vivo and in vitro. Moreover, miR-212-5p mimic treatment attenuated and miR-212-5p inhibitor treatment increased VSMC proliferation and migration. Additionally, miR-212-5p mimic treatment suppressed VSMC contraction and related gene expression [Ras homolog gene family member A (RhoA) and Rho-associated protein kinase 2], while miR-212-5p inhibitor treatment exerted opposite effects. Bioinformatics analysis revealed that platelet-activating factor acetylhydrolase 1B2 (PAFAH1B2) is a target of miR-212-5p. miR-212-5p mimic treatment significantly reduced and miR-212-5p inhibitor treatment increased PAFAH1B2 expression. Furthermore, PAFAH1B2 expression was decreased in angiotensin II-treated aortic tissues and VSMCs. PAFAH1B2 was ubiquitously expressed in most adult rat tissues. In the vasculature, PAFAH1B2 was only distributed in the cytoplasm. PAFAH1B2 overexpression decreased A10 cell proliferation, while PAFAH1B2 knockdown increased A10 cell proliferation and cyclin D1 mRNA levels. PAFAH1B2 knockdown stimulated VSMC contraction and RhoA expression. These results suggest that miR-212-5p and PAFAH1B2 are novel negative regulators of VSMC proliferation, migration, and contraction in hypertension.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , MicroRNAs/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterase/antagonistas & inibidores , 1-Alquil-2-acetilglicerofosfocolina Esterase/genética , Angiotensina II/farmacologia , Animais , Antagomirs/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Ciclina D1/genética , Ciclina D1/metabolismo , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Hipertensão/metabolismo , Hipertensão/patologia , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Contração Muscular/fisiologia , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Remodelação Vascular
8.
EBioMedicine ; 65: 103283, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33714889

RESUMO

BACKGROUND: Osteoarthritis (OA), a disease with whole-joint damage and dysfunction, is the leading cause of disability worldwide. The progressive loss of hyaline cartilage extracellular matrix (ECM) is considered as its hallmark, but its exact pathogenesis needs to be further clarified. MicroRNA(miRNA) contributes to OA pathology and may help to identify novel biomarkers and therapies against OA. Here we identified miR-214-3p as an important regulator of OA. METHODS: qRT-PCR and in situ hybridization were used to detect the expression level of miR-214-3p. The function of miR-214-3p in OA, as well as the interaction between miR-214-3p and its downstream mRNA target (IKBKB), was evaluated by western blotting, immunofluorescence, qRT-PCR and luciferase assay. Mice models were introduced to examine the function and mechanism of miR-214-3p in OA in vivo. FINDINGS: In our study, we found that miR-214-3p, while being down-regulated in inflamed chondrocytes and OA cartilage, regulated ECM metabolism and cell apoptosis in the cartilage. Mechanically, the protective effect of miR-214-3p downregulated the IKK-ß expression and led to the dysfunction of NF-κB signaling pathway. Furthermore, intra-articular injection of miR-214-3p antagomir in mice joints triggered spontaneous cartilage loss while miRNA-214-3p agomir alleviated OA in the experimental mouse models. INTERPRETATION: Decreased miR-214-3p activates the NF-κB signaling pathway and aggravates OA development through targeting IKKß, suggesting miR-214-3p may be a novel therapeutic target for OA. FUNDING: This study was financially supported by grants from the National Natural Science Foundation of China (81,773,532, 81,974,342).


Assuntos
MicroRNAs/metabolismo , NF-kappa B/metabolismo , Osteoartrite/patologia , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Antagomirs/uso terapêutico , Apoptose , Cartilagem/metabolismo , Cartilagem/patologia , Células Cultivadas , Condrócitos/citologia , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Matriz Extracelular/metabolismo , Humanos , Quinase I-kappa B/antagonistas & inibidores , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Interleucina-1beta/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/química , MicroRNAs/genética , Osteoartrite/tratamento farmacológico , Osteoartrite/metabolismo , Interferência de RNA , Transdução de Sinais
9.
Cell Biochem Biophys ; 79(2): 387-396, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33725330

RESUMO

Colorectal cancer (CRC) belongs to one of gastric cancers that half of cases will develop metastasis, causing higher mortality or chemotherapy resistance. In the present study, the long noncoding RNA zinc finger antisense 1 (ZFAS1) was proved to have high expression level in CRC samples and in advanced stages. Additionally, it also indicated that p53 status is associated with ZFAS1 expression. Silencing ZFAS1 reduced both migration and invasion ability of DLD-1 and HCT-116 cells, which is relevant to the EMT process. In addition, it was confirmed that miR-34b, a tumor suppressor miRNA directly targeted ZFAS1 3' untranslated region (3'UTR) and inhibited ZFAS1 expression. Furthermore, miR-34b partially reversed the effect of ZFAS1 on migration and invasion ability in DLD-1 cells. Meanwhile, p53 status changes by overexpression vectors or siRNA turbulent ZFAS1 expression. Besides, it was found that in most cases, the oncogene SOX4 was directly targeted by miR-34b and positive correlated to ZFAS1 expression. Silencing ZFAS1 induced SOX4 expression in DLD-1 cells. Our data demonstrated the functions and mechanisms of ZFAS1 in CRC metastasis, illustrating miR-34b directly targets ZFAS1 and inhibits metastasis ability of CRC cells. SOX4 is also the direct downstream target of miR-34b, and silencing ZFAS1 can inhibit SOX4 though modulating miR-34b.


Assuntos
Neoplasias Colorretais/patologia , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo , Fatores de Transcrição SOXC/metabolismo , Regiões 3' não Traduzidas , Antagomirs/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Transição Epitelial-Mesenquimal , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo , Fatores de Transcrição SOXC/genética , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Regulação para Cima
10.
Cell Biochem Biophys ; 79(2): 397-405, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33743142

RESUMO

BACKGROUND: B7 homolog 3 (B7-H3), a member of the immunoregulatory ligand B7 family, is pivotal in T-cell-mediated immune response. It is widely expressed in diverse human tumors and its high expression indicates the poor prognosis of the patients. Nonetheless, B7-H3's role in colorectal cancer (CRC) needs to be further explored. METHODS: Western blot and immunohistochemistry were employed for detecting B7-H3 protein expression in CRC tissues and cell lines, respectively. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized for detecting B7-H3 mRNA and miR-128 expression levels. CRC cell lines SW620 and HT29 were used to construct B7-H3 overexpression or knockdown cell models, respectively. Cell counting kit-8 (CCK-8), 5-bromo-2'-deoxyuridine (BrdU), and scratch wound healing assays were employed for evaluating the effects of B7-H3 on CRC cell multiplication and migration. Besides, the regulatory relationship between miR-128 and B7-H3 was validated through dual-luciferase reporter gene assay, qRT-PCR, and western blotting. RESULTS: B7-H3 expression level was remarkably elevated in CRC tissues and cell lines, and its high expression level was associated with increased tumor size, positive lymph node metastasis, and increased T stage. In CRC cells, B7-H3 overexpression significantly facilitated the cell multiplication and migration, while B7-H3 knockdown worked oppositely. Moreover, B7-H3 was identified as a target of miR-128, and miR-128 negatively regulated B7-H3 expression in CRC cells. CONCLUSION: B7-H3 expression is upregulated in CRC tissues and cell lines, and B7-H3 participates in promoting the proliferation and migration of CRC cells. Besides, B7-H3 expression is negatively regulated by miR-128 in CRC.


Assuntos
Antígenos B7/metabolismo , Neoplasias Colorretais/patologia , MicroRNAs/metabolismo , Antagomirs/metabolismo , Antígenos B7/antagonistas & inibidores , Antígenos B7/genética , Sequência de Bases , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Alinhamento de Sequência , Taxa de Sobrevida
11.
Cell Prolif ; 54(5): e13026, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33759282

RESUMO

OBJECTIVES: Previously, our investigations demonstrated robust pro-angiogenic potentials of extracellular vesicles secreted by periodontitis-compromised dental pulp stem cells (P-EVs) when compared to those from healthy DPSCs (H-EVs), but the underlying mechanism remains unknown. MATERIALS AND METHODS: Here, circulating microRNAs (miRNAs) specifically found in P-EVs (compared with H-EVs) were identified by Agilent miRNA microarray analysis, and the roles of the candidate miRNA in P-EV-enhanced cell angiogenesis were confirmed by cell transfection and RNA interference methods. Next, the direct binding affinity between the candidate miRNA and its target gene was evaluated by luciferase reporter assay. CCK-8, transwell/scratch wound healing and tube formation assays were established to investigate the proliferation, migration, and tube formation abilities of endothelial cells (ECs). Western blot was employed to measure the protein levels of Hedgehog/Gli1 signalling pathway components and angiogenesis-related factors. RESULTS: The angiogenesis-related miRNA miR-378a was found to be enriched in P-EVs, and its role in P-EV-enhanced cell angiogenesis was confirmed, wherein Sufu was identified as a downstream target gene of miR-378a. Functionally, silencing of Sufu stimulated EC proliferation, migration and tube formation by activating Hedgehog/Gli1 signalling. Further, we found that incubation with P-EVs enabled the transmission of P-EV-contained miR-378a to ECs. Subsequently, the expressions of Sufu, Gli1 and vascular endothelial growth factor in ECs were significantly influenced by P-EV-mediated miR-378a transmission. CONCLUSIONS: These data suggest that P-EVs carrying miR-378a promote EC angiogenesis by downregulating Sufu to activate the Hedgehog/Gli1 signalling pathway. Our findings reveal a crucial role for EV-derived miR-378a in cell angiogenesis and hence offer a new target for modifying stem cells and their secreted EVs to enhance vessel regenerative potential.


Assuntos
Vesículas Extracelulares/metabolismo , MicroRNAs/metabolismo , Neovascularização Fisiológica , Proteínas Repressoras/metabolismo , Transdução de Sinais , Antagomirs/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Polpa Dentária/citologia , Polpa Dentária/metabolismo , Vesículas Extracelulares/genética , Proteínas Hedgehog/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Periodontite/metabolismo , Periodontite/patologia , Piridinas/farmacologia , Pirimidinas/farmacologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Células-Tronco/citologia , Células-Tronco/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo
12.
Am J Physiol Heart Circ Physiol ; 320(4): H1348-H1360, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33416455

RESUMO

Viral myocarditis (VMC) is a life-threatening disease characterized by severe cardiac inflammation generally caused by coxsackievirus B3 (CVB3) infection. Several microRNAs (miRNAs or miRs) are known to play crucial roles in the pathogenesis of VMC. The study aimed to decipher the role of miR-30a-5p in the underlying mechanisms of VMC pathogenesis. We first quantified miR-30a-5p expression in a CVB3-induced mouse VMC model. The physiological characteristics of mouse cardiac tissues were then detected by hematoxylin and eosin (HE) and Picrosirius red staining. We established the correlation between miR-30a-5p and SOCS1, using dual-luciferase gene assay and Pearson's correlation coefficient. The expression of inflammatory factors (IFN-γ, IL-6, IL-10, and IL-13), M1 polarization markers [TNF-α, inducible nitric oxide synthase (iNOS)], M2 polarization markers (Arg-1, IL-10), and myocardial hypertrophy markers [atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP)] was detected by RT-qPCR and Western blot analysis. miR-30a-5p was found to be highly expressed in VMC mice. Silencing of miR-30a-5p improved the cardiac function index and reduced heart weight-to-body weight ratio, myocardial tissue pathological changes and fibrosis degree, serological indexes, as well as proinflammatory factor levels, while enhancing anti-inflammatory factor levels in VMC mice. Furthermore, silencing of miR-30a-5p inhibited M1 polarization of macrophages while promoting M2 polarization in vivo and in vitro. SOCS1 was a target gene of miR-30a-5p, and the aforementioned cardioprotective effects of miR-30a-5p silencing were reversed upon silencing of SOCS1. Overall, this study shows that silencing of miR-30a-5p may promote M2 polarization of macrophages and improve cardiac injury following VMC via SOCS1 upregulation, constituting a potential therapeutic target for VMC treatment.NEW & NOTEWORTHY We found in this study that microRNA (miR)-30a-5p inhibition might improve cardiac injury following viral myocarditis (VMC) by accelerating M2 polarization of macrophages via SOCS1 upregulation. Furthermore, the anti-inflammatory mechanisms of miR-30a-5p inhibition may contribute to the development of new therapeutic strategies for VMC.


Assuntos
Infecções por Coxsackievirus/terapia , Inativação Gênica , Terapia Genética , Macrófagos/metabolismo , MicroRNAs/genética , Miocardite/terapia , Miócitos Cardíacos/metabolismo , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Animais , Antagomirs/genética , Antagomirs/metabolismo , Células Cultivadas , Infecções por Coxsackievirus/genética , Infecções por Coxsackievirus/metabolismo , Infecções por Coxsackievirus/virologia , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Enterovirus Humano B/patogenicidade , Mediadores da Inflamação/metabolismo , Macrófagos/virologia , Masculino , Camundongos Endogâmicos BALB C , MicroRNAs/metabolismo , Miocardite/genética , Miocardite/metabolismo , Miocardite/virologia , Miócitos Cardíacos/patologia , Miócitos Cardíacos/virologia , Fenótipo , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina/genética
13.
Microvasc Res ; 135: 104134, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33428882

RESUMO

BACKGROUND: Clinical data show that aneurysm rupture causes high mortality in aged men. MicroRNAs (miRNAs) were reported to regulate endothelial progenitor cells (EPCs) which play a vital role in repairing endothelial damage and maintaining vascular integrity. This study identified a novel miRNA regulator for the functions of EPCs in aneurysm repair. METHODS: Abdominal aortic aneurysm (AAA) model was established on Sprague-Dawley rats which later underwent antagomiR-222 treatment. The histopathological changes of AAA rats were examined by hematoxylin-eosin staining. Flow cytometry was performed to quantify EPCs in peripheral blood and identify EPCs isolated from the rat femur. The potential target of miR-222-3p was predicted by TargetScan v7.2 and validated by Dual-luciferase reporter assay. The effects of miR-222-3p and ADIPOR1 on the migration, invasion and tube formation of EPCs were evaluated by wound healing, Transwell and tube formation assays. The expressions of miR-222-3p and ADIPOR1 in aortic aneurysm tissues and EPCs were assessed by qRT-PCR or Western blot. RESULTS: AAA exhibited histopathological abnormality, a decreased number of EPCs in the peripheral blood and an increased miR-222-3p expression. AntagomiR-222 injection reversed all these phenomena in AAA rats. Upregulating miR-222-3p expression inhibited the migration, invasion, and tube formation of EPCs, and the expressions of ADIPOR1 and phosphorylated-AMKP, while downregulating miR-222-3p expression exerted opposite effects in EPCs. ADIPOR1 was identified as a target gene of miR-222-3p. Overexpressing ADIPOR1 abrogated the effects of miR-222-3p upregulation on EPCs. CONCLUSION: Downregulated miR-222-3p prompted the migration, invasion and recruitment of EPCs by targeting ADIPOR1-induced AMKP activation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/enzimologia , Movimento Celular , Células Progenitoras Endoteliais/enzimologia , MicroRNAs/metabolismo , Neovascularização Fisiológica , Receptores de Adiponectina/metabolismo , Animais , Antagomirs/genética , Antagomirs/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo , Células Progenitoras Endoteliais/patologia , Ativação Enzimática , Humanos , Masculino , MicroRNAs/genética , Fosforilação , Ratos Sprague-Dawley , Receptores de Adiponectina/genética , Transdução de Sinais
14.
Development ; 148(5)2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33472846

RESUMO

In mammals, sperm-borne regulators can be transferred to oocytes during fertilization and have different effects on the formation of pronuclei, the first cleavage of zygotes, the development of preimplantation embryos and even the metabolism of individuals after birth. The regulatory role of sperm microRNAs (miRNAs) in the development of bovine preimplantation embryos has not been reported in detail. By constructing and screening miRNA expression libraries, we found that miR-202 was highly enriched in bovine sperm. As a target gene of miR-202, co-injection of SEPT7 siRNA can partially reverse the accelerated first cleavage of bovine embryos caused by miR-202 inhibitor. In addition, both a miR-202 mimic and SEPT7 siRNA delayed the first cleavage of somatic cell nuclear transfer (SCNT) embryos, suggesting that miR-202-SEPT7 mediates the delay of first cleavage of bovine embryos. By further exploring the relationship between miR-202/SEPT7, HDAC6 and acetylated α-tubulin during embryonic development, we investigated how sperm-borne miR-202 regulates the first cleavage process of bovine embryos by SEPT7 and demonstrate the potential of sperm-borne miRNAs to improve the efficiency of SCNT.


Assuntos
Citoesqueleto/metabolismo , Embrião de Mamíferos/metabolismo , MicroRNAs/metabolismo , Septinas/metabolismo , Regiões 3' não Traduzidas , Acetilação , Animais , Antagomirs/metabolismo , Bovinos , Desenvolvimento Embrionário , Feminino , Fertilização In Vitro , Desacetilase 6 de Histona/metabolismo , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Gravidez , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Septinas/antagonistas & inibidores , Septinas/genética , Espermatozoides/metabolismo , Tubulina (Proteína)/metabolismo , Zigoto/metabolismo
15.
Cell Prolif ; 54(2): e12976, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33393124

RESUMO

BACKGROUND: In mammals, early pregnancy is a critical vulnerable period during which complications may arise, including pregnancy failure. Establishment of a maternal endometrial acceptance phenotype is a prerequisite for semiheterogeneous embryo implantation, comprising the rate-limiting step of early pregnancy. METHODS: Confocal fluorescence, immunohistochemistry and western blot for nuclear and cytoplasmic protein were used to examine the activation of yes-associated protein (YAP) in uterine tissue and primary endometrial cells. The target binding between miR16a and YAP was verified by dual-luciferase reporter gene assay. The mouse pregnancy model and pseudopregnancy model were used to investigate the role of YAP in the maternal uterus during early pregnancy in vivo. RESULTS: We showed that YAP translocates into the nucleus in the endometrium of cattle and mice during early pregnancy. Mechanistically, YAP acts as a mediator of ECM rigidity and cell density, which requires the actomyosin cytoskeleton and is partially dependent on the Hippo pathway. Furthermore, we found that the soluble factor IFNτ, which is a ruminant pregnancy recognition factor, also induced activation of YAP by reducing the expression of miR-16a. CONCLUSIONS: This study revealed that activation of YAP is necessary for early pregnancy in bovines because it induced cell proliferation and established an immunosuppressive local environment that allowed conceptus implantation into the uterine epithelium.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ciclo Celular/metabolismo , Endométrio/metabolismo , Matriz Extracelular/metabolismo , Interferon Tipo I/metabolismo , Proteínas da Gravidez/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Antagomirs/metabolismo , Bovinos , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/genética , Endométrio/citologia , Molécula de Adesão da Célula Epitelial/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Interferon Tipo I/farmacologia , Masculino , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas Musculares/metabolismo , Gravidez , Proteínas da Gravidez/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Útero/metabolismo , Útero/patologia
16.
Life Sci ; 264: 118666, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33130085

RESUMO

AIMS: To clarify the role of the miR-125a/VDR axis in the regulation of autophagic flux in hepatocytes and liver fibrosis. MAIN METHODS: The effects of the miR-125a/VDR axis on hepatic fibrosis and its underlying mechanisms were investigated in a carbon tetrachloride (CCl4)-induced mouse model and patients with liver cirrhosis by immunohistochemistry, real-time PCR, Western blotting, and luciferase reporter assay. KEY FINDINGS: The degree of fibrosis in patients with liver cirrhosis was negatively correlated with VDR expression and autophagic flux in hepatocytes. Luciferase reporter assays confirmed that VDR is a direct target of miR-125a, which was positively correlated with the degree of fibrosis but negatively correlated with the autophagic flux and VDR expression in human liver cirrhosis tissue. miR-125a-antagomir-GFP AAV treatment partially restored VDR expression and autophagic flux and abrogated fibrosis in the liver of CCL4-induced mouse. In addition, knockdown of VDR abrogated the protective effect of miR-125a-antagomir-GFP AAV on autophagic flux and against liver fibrosis in the CCL4-induced mouse model. SIGNIFICANCE: Our study for the first time identified the miR-125a/VDR axis as involved in the occurrence and development of liver fibrosis by regulating autophagic flux in hepatocytes.


Assuntos
Autofagia/genética , Cirrose Hepática/genética , Cirrose Hepática/patologia , MicroRNAs/metabolismo , Receptores de Calcitriol/metabolismo , Animais , Antagomirs/metabolismo , Sequência de Bases , Tetracloreto de Carbono , Dependovirus/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica , Proteínas de Fluorescência Verde/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética
17.
Cell Mol Life Sci ; 78(6): 2987-3003, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33206203

RESUMO

The pathogenesis of obesity-related metabolic diseases has been linked to the inflammation of white adipose tissue (WAT), but the molecular interconnections are still not fully understood. MiR-146a controls inflammatory processes by suppressing pro-inflammatory signaling pathways. The aim of this study was to characterize the role of miR-146a in obesity and insulin resistance. MiR-146a-/- mice were subjected to a high-fat diet followed by metabolic tests and WAT transcriptomics. Gain- and loss-of-function studies were performed using human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes. Compared to controls, miR-146a-/- mice gained significantly more body weight on a high-fat diet with increased fat mass and adipocyte hypertrophy. This was accompanied by exacerbated liver steatosis, insulin resistance, and glucose intolerance. Likewise, adipocytes transfected with an inhibitor of miR-146a displayed a decrease in insulin-stimulated glucose uptake, while transfecting miR-146a mimics caused the opposite effect. Natriuretic peptide receptor 3 (NPR3) was identified as a direct target gene of miR-146a in adipocytes and CRISPR/Cas9-mediated knockout of NPR3 increased insulin-stimulated glucose uptake and enhanced de novo lipogenesis. In summary, miR-146a regulates systemic and adipocyte insulin sensitivity via downregulation of NPR3.


Assuntos
Resistência à Insulina , MicroRNAs/metabolismo , Receptores do Fator Natriurético Atrial/metabolismo , Adipócitos/citologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Antagomirs/metabolismo , Peso Corporal , Dieta Hiperlipídica , Fígado Gorduroso/patologia , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina/genética , Lipogênese , Fígado/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo , Triglicerídeos/metabolismo
18.
Life Sci ; 269: 118817, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33275986

RESUMO

AIMS: This study aimed to elucidate the role of microRNAs (miRNAs) during myocardial infarction (MI) development in vivo and in vitro. MAIN METHODS: Differentially expressed miRNAs between heart tissue from the MI mouse model and the control mouse were identified via microarray. Quantitative PCR (qPCR) and western blotting (WB) were performed to examine the expression levels of miRNAs and proteins, respectively. EdU-staining and colony formation assay were performed to assess cell viability and growth. Annexin V- and PI-staining-based flow cytometry was used to assess cell apoptosis. An MI mouse model was also established to study the function of miR-1278 in vivo. KEY FINDINGS: The levels of miR-1278 were reduced in the infarct regions of heart tissues of the MI mouse model and in H2O2-treated newborn murine ventricular cardiomyocytes (NMVCs) compared to those in the heart tissues of healthy mice and non-treated NMVCs. H2O2 treatment suppressed the proliferation of NMVCs, while miR-1278 upregulation improved it. Moreover, we found that miR-1278 inhibited the upregulation of IL-22 and CXCL14 expression in H2O2-treated NMVCs by directly binding with the 3'-UTRs of both IL-22 and CXCL14. Furthermore, restoration of IL-22 and CXCL14 in H2O2-treated NMVCs promoted miR-1278-induced inflammation and apoptosis. Administration of agomiR-1278 to the MI mouse model significantly improved cardiac activity. SIGNIFICANCE: Collectively, our findings illustrate that the expression of miR-1278 is low in H2O2-treated NMVCs and post-MI cardiac tissues, and the overexpression of miR-1278 in these protects against cell death by modulating IL-22 and CXCL14 expression.


Assuntos
Quimiocinas CXC/metabolismo , Inflamação/genética , Interleucinas/metabolismo , MicroRNAs/metabolismo , Isquemia Miocárdica/genética , Miócitos Cardíacos/patologia , Regiões 3' não Traduzidas/genética , Animais , Animais Recém-Nascidos , Antagomirs/metabolismo , Apoptose/efeitos dos fármacos , Sequência de Bases , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação para Baixo/genética , Feminino , Testes de Função Cardíaca , Ventrículos do Coração/patologia , Peróxido de Hidrogênio/toxicidade , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Miócitos Cardíacos/metabolismo
19.
J Cereb Blood Flow Metab ; 41(3): 530-545, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32248729

RESUMO

RNA-binding protein fox-1 homolog 1 (Rbfox-1), an RNA-binding protein in neurons, is thought to be associated with many neurological diseases. To date, the mechanism on which Rbfox-1 worsens secondary cell death in ICH remains poorly understood. In this study, we aimed to explore the role of Rbfox-1 in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) and to identify its underlying mechanisms. We found that the expression of Rbfox-1 in neurons was significantly increased after ICH, which was accompanied by increases in the binding of Rbfox-1 to Ca2+/calmodulin-dependent protein kinase II (CaMKIIα) mRNA and the protein level of CaMKIIα. In addition, when exposed to exogenous upregulation or downregulation of Rbfox-1, the protein level of CaMKIIα showed a concomitant trend in brain tissue, which further suggested that CaMKIIα is a downstream-target protein of Rbfox-1. The upregulation of both proteins caused intracellular-Ca2+ overload and neuronal degeneration, which exacerbated brain damage. Furthermore, we found that Rbfox-1 promoted the expression of CaMKIIα via blocking the binding of micro-RNA-124 to CaMKIIα mRNA. Thus, Rbfox-1 is expected to be a promising therapeutic target for SBI after ICH.


Assuntos
Lesões Encefálicas/patologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Hemorragias Intracranianas/complicações , MicroRNAs/metabolismo , Fatores de Processamento de RNA/metabolismo , Animais , Antagomirs/metabolismo , Apoptose/efeitos dos fármacos , Comportamento Animal , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas/etiologia , Lesões Encefálicas/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Células Cultivadas , Disfunção Cognitiva/etiologia , Modelos Animais de Doenças , Hemorragias Intracranianas/induzido quimicamente , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Neurônios/citologia , Neurônios/metabolismo , Oxiemoglobinas/farmacologia , Interferência de RNA , Fatores de Processamento de RNA/antagonistas & inibidores , Fatores de Processamento de RNA/genética , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley
20.
J Cereb Blood Flow Metab ; 41(3): 641-655, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32501158

RESUMO

The mechanism of early blood-brain barrier (BBB) disruption after stroke has been intensively studied but still not fully understood. Here, we report that microRNA-30a (miR-30a) could mediate BBB damage using both cellular and animal models of ischemic stroke. In the experiments in vitro, inhibition of miR-30a decreased BBB permeability, prevented the degradation of tight junction proteins, and reduced intracellular free zinc in endothelial cells. We found that the zinc transporter ZnT4 was a direct target of negative regulation by miR-30a, and ZnT4/zinc signaling pathway contributed significantly to miR-30a-mediated BBB damage. Consistent with these in vitro findings, treatment with miR-30a inhibitor reduced zinc accumulation, increased the expression of ZnT4, and prevented the loss of tight junction proteins in microvessels of ischemic animals. Furthermore, inhibition of miR-30a, even at 90 min post onset of middle cerebral artery occlusion, prevented BBB damage, reduced infarct volume, and ameliorated neurological deficits. Together, our findings provide novel insights into the mechanisms of cerebral ischemia-induced BBB disruption and indicate miR-30a as a regulator of BBB function that can be an effective therapeutic target for ischemic stroke.


Assuntos
Barreira Hematoencefálica/metabolismo , Isquemia Encefálica/patologia , Proteínas de Transporte de Cátions/metabolismo , MicroRNAs/metabolismo , Regiões 3' não Traduzidas , Animais , Antagomirs/metabolismo , Antagomirs/farmacologia , Antagomirs/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Proteínas de Transporte de Cátions/antagonistas & inibidores , Proteínas de Transporte de Cátions/genética , Linhagem Celular , Sobrevivência Celular , Claudina-5/metabolismo , Modelos Animais de Doenças , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Camundongos , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Microvasos/metabolismo , Ocludina/metabolismo , Permeabilidade/efeitos dos fármacos , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Zinco/metabolismo
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