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1.
Life Sci ; 240: 117077, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31751586

RESUMO

Importance of dysregulation and expression of microRNAs (miRNAs) has been confiemed in many disorders comprising cancer. In this way, different approaches to induce reprogramming from one cell type to another in oerder to control the cell normal mechanisem, comprising microRNAs, combinatorial small molecules, exosome-mediated reprogramming, embryonic microenvironment and also lineage-specific transcription agents, are involved in cell situation. Meaningly, besides the above factors, microRNAs are so special and have an impressive role in cell reprogramming. One of the main applications of cancer cell reprogramming is it's ability in therapeutic approach. Many insights in reprogramming mechanism have been recommended, and determining improvment has been aknolwged to develop reprogramming efficiency and possibility, permiting it to appear as practical therapy against all cancers. Conspiciously, the recent studies on the fluctuations and performance of microRNAs,small endogenous non-coding RNAs, as notable factors in carcinogenesis and tumorigenesis, therapy resistance and metastasis and as new non-invasive cancer biomarkers has a remarkable attention. This is due to their unique dysregulated signatures throughout tumor progression. Recognising miRNAs signatures capable of anticipating therapy response and metastatic onset in cancers might enhance diagnosis and therapy. According to the growing reports on miRNAs as novel non-invasive biomarkers in various cancers as a main regulators of cancers drug resistance or metastasis, the quest on whether some miRNAs have the ability to regulate both simultaneously is inevitable, yet understudied. The combination of genetic diagnosis using next generation sequencing and targeted therapy may contribute to the effective precision medicine for cancer therapy. Here, we want to review the practical application of microRNAs performance in carcinogenesis and tumorigenesis in cancer therapy.


Assuntos
Carcinogênese/genética , MicroRNAs/genética , MicroRNAs/uso terapêutico , Neoplasias/terapia , Animais , Regulação Neoplásica da Expressão Gênica , Terapia Genética , Humanos
2.
Folia Histochem Cytobiol ; 57(4): 168-178, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31825519

RESUMO

INTRODUCTION: Sepsis-induced acute lung injury (ALI) is an inflammatory process involved with simultaneous production of inflammatory cytokines and chemokines. In this study, we investigated the regulatory role of miR-539-5p in sepsis-induced ALI using a mouse model of cecal ligation puncture (CLP) and an in vitro model of primary murine pulmonary microvascular endothelial cells (MPVECs). MATERIAL AND METHODS: Adult male C57BL/6 mice were intravenously injected with or without miR-539-5p agomir or scrambled control one week before CLP operation. MPVECs were transfected with miR-539-5p mimics or control mimics, followed by lipopolysaccharide (LPS) stimulation. ROCK1 was predicted and confirmed as a direct target of miR-539-5p using dual-luciferase reporter assay. In rescue experiment, MPVECs were co-transfected with lentiviral vector expressing ROCK1 (or empty vector) and miR-539-5p mimics 24 h before LPS treatment. The transcriptional activity of caspase-3, the apoptosis ratio, the levels of miR-539-5p, interleukin-1b (IL-1b), interleukin-6 (IL-6), and ROCK1 were assessed. RESULTS: Compared to sham group, mice following CLP showed pulmonary morphological abnormalities, elevated production of IL-1b and IL-6, and increased caspase-3 activity and apoptosis ratio in the lung. In MPVECs, LPS stimulation resulted in a significant induction of inflammatory cytokine levels and apoptosis compared to untreated cells. The overexpression of miR-539-5p in septic mice alleviated sepsis-induced pulmonary injury, apoptosis, and inflammation. MiR-539-5p also demonstrated anti-apoptotic and anti-inflammatory effect in LPS-treated MPVECs. The upregulation of ROCK1 in MPVECs recovered miR-539-5p-suppressed caspase-3 activity and proinflammatory cytokine production. CONCLUSION: In conclusion, miR-539-5p alleviated sepsis-induced ALI via suppressing its downstream target ROCK1, suggesting a therapeutic potential of miR-539-5p for the management of sepsis-induced ALI.


Assuntos
Lesão Pulmonar Aguda/terapia , MicroRNAs/uso terapêutico , Quinases Associadas a rho/metabolismo , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Linhagem Celular , Regulação para Baixo , Inflamação/terapia , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Sepse/induzido quimicamente , Sepse/complicações , Transfecção
3.
Acta Cir Bras ; 34(8): e201900802, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618402

RESUMO

PURPOSE: To reveal the function of miR-134 in myocardial ischemia. METHODS: Real-time PCR and western blotting were performed to measure the expression of miR-134, nitric oxide synthase 3 (NOS3) and apoptotic-associated proteins. Lactic dehydrogenase (LDH) assay, cell counting kit-8 (CCK-8), Hoechst 33342/PI double staining and flow cytometry assay were implemented in H9c2 cells, respectively. MiR-134 mimic/inhibitor was used to regulate miR-134 expression. Bioinformatic analysis and luciferase reporter assay were utilized to identify the interrelation between miR-134 and NOS3. Rescue experiments exhibited the role of NOS3. The involvement of PI3K/AKT was assessed by western blot analysis. RESULTS: MiR-134 was high regulated in the myocardial ischemia model, and miR-134 mimic/inhibitor transfection accelerated/impaired the speed of cell apoptosis and attenuated/exerted the cell proliferative prosperity induced by H/R regulating active status of PI3K/AKT signaling. LDH activity was also changed due to the different treatments. Moreover, miR-134 could target NOS3 directly and simultaneously attenuated the expression of NOS3. Co-transfection miR-134 inhibitor and pcDNA3.1-NOS3 highlighted the inhibitory effects of miR-134 on myocardial H/R injury. CONCLUSION: This present work puts insights into the crucial effects of the miR-134/NOS3 axis in myocardial H/R injury, delivering a potential therapeutic technology in future.


Assuntos
Hipóxia/metabolismo , MicroRNAs/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Proliferação de Células/efeitos dos fármacos , MicroRNAs/genética , MicroRNAs/uso terapêutico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/patologia , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Transdução de Sinais/efeitos dos fármacos
5.
Chem Commun (Camb) ; 55(63): 9363-9366, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31317136

RESUMO

We developed a biodegradable, oncosensitive, megamer-based delivery system for miRNA therapy. The miRNA nanotherapeutics, activatable by stepwise stimulation of acidity and reduction mimicking tumor microenvironment, efficiently improve liver-specific miR-122 expression, increasing the possibility of translational application of miR-122 therapy against liver cancer.


Assuntos
Portadores de Fármacos/química , MicroRNAs/química , Nanopartículas/química , Polietilenoglicóis/química , Animais , Linhagem Celular Tumoral , Dendrímeros/química , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Camundongos , Camundongos Nus , MicroRNAs/metabolismo , MicroRNAs/uso terapêutico , Transplante Heterólogo
6.
Nat Commun ; 10(1): 3184, 2019 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-31320641

RESUMO

Thoracic aortic dissection (TAD) is an aggressive vascular disease that requires early diagnosis and effective treatment. However, due to the particular vascular structure and narrowness of lesion location, there are no effective drug delivery systems for the therapy of TAD. Here, we report a multifunctional delivery nanosystem (TP-Gd/miRNA-ColIV) composed of gadolinium-chelated tannic acid (TA), low-toxic cationic PGEA (ethanolamine-aminated poly(glycidyl methacrylate)) and type IV collagen targeted peptide (ColIV) for targeted nucleic acid therapy, early diagnosis and noninvasive monitoring of TAD. Such targeted therapy with miR-145 exhibits impressive performances in stabilizing the vascular structures and preventing the deterioration of TAD. After the treatment with TP-Gd/miR-145-ColIV, nearly no dissection occurs in the thoracic aortic arches of the mice with TAD model. Moreover, TP-Gd/miRNA-ColIV also demonstrates good magnetic resonance imaging (MRI) ability and can be used to noninvasively monitor the development conditions of TAD.


Assuntos
Aneurisma Dissecante/terapia , Aneurisma da Aorta Torácica/terapia , Sistemas de Liberação de Medicamentos/métodos , Terapia Genética/métodos , MicroRNAs/administração & dosagem , MicroRNAs/uso terapêutico , Aneurisma Dissecante/patologia , Animais , Aneurisma da Aorta Torácica/patologia , Células Cultivadas , Colágeno Tipo IV/química , Gadolínio/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Ácidos Polimetacrílicos/química , Taninos/química , Artérias Torácicas/patologia
7.
EBioMedicine ; 45: 646-654, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31300345

RESUMO

MicroRNA-134 is a brain-enriched small noncoding RNA that has been implicated in diverse neuronal functions, including regulating network excitability. Increased expression of microRNA-134 has been reported in several experimental epilepsy models and in resected brain tissue from temporal lobe epilepsy patients. Rodent studies have demonstrated that reducing microRNA-134 expression in the brain using antisense oligonucleotides can increase seizure thresholds and attenuate status epilepticus. Critically, inhibition of microRNA-134 after status epilepticus can potently reduce the occurrence of spontaneous recurrent seizures. Altered plasma levels of microRNA-134 have been reported in epilepsy patients, suggesting microRNA-134 may have diagnostic value as a biomarker. This review summarises findings on the cellular functions of microRNA-134, as well as the preclinical evidence supporting anti-seizure and disease-modifying effects of targeting microRNA-134 in epilepsy. Finally, we draw attention to unanswered questions and some of the challenges and opportunities involved in preclinical development of a microRNA-based oligonucleotide treatment for epilepsy.


Assuntos
Epilepsia/terapia , MicroRNAs/genética , Neurônios/metabolismo , Convulsões/terapia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Epilepsia/genética , Epilepsia/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , MicroRNAs/antagonistas & inibidores , MicroRNAs/uso terapêutico , Neurônios/patologia , Oligonucleotídeos Antissenso/genética , Oligonucleotídeos Antissenso/uso terapêutico , Convulsões/genética
8.
Int J Mol Sci ; 20(13)2019 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-31284594

RESUMO

Although many diagnostic and therapeutic modalities for pancreatic cancer have been proposed, an urgent need for improved therapeutic strategies remains. Oligonucleotide therapeutics, such as those based on antisense RNAs, small interfering RNA (siRNA), microRNA (miRNA), aptamers, and decoys, are promising agents against pancreatic cancer, because they can identify a specific mRNA fragment of a given sequence or protein, and interfere with gene expression as molecular-targeted agents. Within the past 25 years, the diversity and feasibility of these drugs as diagnostic or therapeutic tools have dramatically increased. Several clinical and preclinical studies of oligonucleotides have been conducted for patients with pancreatic cancer. To support the discovery of effective diagnostic or therapeutic options using oligonucleotide-based strategies, in the absence of satisfactory therapies for long-term survival and the increasing trend of diseases, we summarize the current clinical trials of oligonucleotide therapeutics for pancreatic cancer patients, with underlying preclinical and scientific data, and focus on the possibility of oligonucleotides for targeting pancreatic cancer in clinical implications.


Assuntos
Oligonucleotídeos Antissenso/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Aptâmeros de Nucleotídeos/uso terapêutico , Ensaios Clínicos como Assunto , Humanos , MicroRNAs/uso terapêutico , RNA Interferente Pequeno/uso terapêutico
9.
Scand J Immunol ; 90(5): e12810, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31325389

RESUMO

MicroRNAs (miRNAs) play a vital role in the occurrence and development of many human diseases, including systemic lupus erythematosus (SLE). SLE is an autoimmune disease characterized by the production of autoantibodies against nuclear antigens and multiorgan involvement. Study of miRNAs involved in SLE provides new insights into the pathogenesis of SLE and might lead to the identification of new therapeutic interventions. The aim of this study was to investigate the effect of miR-183 injection on the progression of SLE by using MRL/lpr mouse model. The expression levels of miR-183 and mTOR mRNA were detected by quantitative real-time PCR assay. The effect of miR-183 on the course of spontaneous disease progression in the MRL/lpr mice was examined by intraperitoneal injection of miR-183 into mice and followed by monitoring lifespan, anti-dsDNA antibody levels, urinary albumin levels, blood urea nitrogen (BUN) levels, and Tregs and Th17 cell population. We found that miR-183 injection resulted in reduction of anti-DNA antibody and immune complex component levels, restoration of Tregs and Th17 cell population and prolongation of survival. Our findings suggest that miR-183 injection may serve as an effective therapeutic treatment for delaying or easing pathologic features of SLE.


Assuntos
Nefrite Lúpica/terapia , MicroRNAs/genética , MicroRNAs/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/genética , Adulto , Albuminúria/urina , Animais , Anticorpos Antinucleares/sangue , Nitrogênio da Ureia Sanguínea , Modelos Animais de Doenças , Feminino , Humanos , Nefrite Lúpica/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/genética , Linfócitos T Reguladores/imunologia , Serina-Treonina Quinases TOR/metabolismo , Células Th17/imunologia
10.
Medicina (Kaunas) ; 55(8)2019 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-31357735

RESUMO

The upgraded knowledge of tumor biology and microenviroment provides information on differences in neoplastic and normal cells. Thus, the need to target these differences led to the development of novel molecules (targeted therapy) active against the neoplastic cells' inner workings. There are several types of targeted agents, including Small Molecules Inhibitors (SMIs), monoclonal antibodies (mAbs), interfering RNA (iRNA) molecules and microRNA. In the clinical practice, these new medicines generate a multilayered step in pharmacokinetics (PK), which encompasses a broad individual PK variability, and unpredictable outcomes according to the pharmacogenetics (PG) profile of the patient (e.g., cytochrome P450 enzyme), and to patient characteristics such as adherence to treatment and environmental factors. This review focuses on the use of targeted agents in-human phase I/II/III clinical trials in cancer-hematology. Thus, it outlines the up-to-date anticancer drugs suitable for targeted therapies and the most recent finding in pharmacogenomics related to drug response. Besides, a summary assessment of the genotyping costs has been discussed. Targeted therapy seems to be an effective and less toxic therapeutic approach in onco-hematology. The identification of individual PG profile should be a new resource for oncologists to make treatment decisions for the patients to minimize the toxicity and or inefficacy of therapy. This could allow the clinicians to evaluate benefits and restrictions, regarding costs and applicability, of the most suitable pharmacological approach for performing a tailor-made therapy.


Assuntos
Antineoplásicos/uso terapêutico , Reparo Gênico Alvo-Dirigido/métodos , Antineoplásicos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Humanos , MicroRNAs/farmacologia , MicroRNAs/uso terapêutico , Vírus Oncolíticos , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , Literatura de Revisão como Assunto , Reparo Gênico Alvo-Dirigido/estatística & dados numéricos
11.
Gene ; 706: 77-83, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31048070

RESUMO

Therapeutic induction of fetal hemoglobin (HbF) is one of the most promising approaches to ameliorate the severity of hemoglobinopathies like ß-thalassemia and sickle cell anemia. Although several pharmacological agents have been investigated for HbF induction in adults, the majority of these are associated with significant side-effects. While drug repurposing is known to open new doors for the use of approved drugs in unexplored clinical conditions, the primary challenge lies in identifying such candidates. In this study, we aimed to identify repurposing candidates for HbF induction using a novel in silico approach utilizing microRNA-pathway-drug relationships. A computational drug repurposing strategy identified several unique candidates for HbF induction; among which Curcumin, Ginsenoside, Valproate, and Vorinostat were found to be most suitable for future trials. This study identified new drug repurposing candidates for HbF induction and demonstrates an easily adaptable methodology that can be used for other pathophysiological conditions.


Assuntos
Hemoglobina Fetal/biossíntese , Perfilação da Expressão Gênica/métodos , Hemoglobinopatias/genética , Anemia Falciforme/genética , Simulação por Computador , Reposicionamento de Medicamentos/métodos , Hemoglobinopatias/fisiopatologia , Hemoglobinas/biossíntese , Hemoglobinas/metabolismo , Humanos , MicroRNAs/genética , MicroRNAs/uso terapêutico , Transcriptoma/genética , Talassemia beta/genética
12.
J Orthop Surg Res ; 14(1): 118, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053150

RESUMO

OBJECTIVE: Osteoarthritis (OA) is a prevalent degenerative disease caused by various factors. MicroRNAs are important regulators in OA. MiR-21-5p expression is decreased in OA cartilage, but the effects of modulating miR-21-5p on cartilage regeneration are unknown. Therefore, our aim was to investigate the effects of miR-21-5p on cartilage metabolism of OA chondrocytes. DESIGN: We used IL-1ß (10 ng/ml) to mimic OA chondrocytes. OA chondrocytes were transfected with miR-21-5p, the gene expression of COL2A1, MMP13, and ADAMTS5 was detected by qPCR. At the same time, COL2A1, MMP13, and ADAMTS5 were analyzed at the protein level by Western blot. CCK8 measured the cell's viability and SA-ß-gal detected the cell's senescence. RESULTS: Upregulation of miR-21-5p had increased COL2A1 expression and decreased MM P13 and ADAMTS5 expression, which were in accord with Western blot data. SA-ß-gal activity significantly increased, the viability was decreased in OA chondrocytes, and upregulation of miR-21-5p can decrease the SA-ß-gal activity and increase cell viability. CONCLUSION: MiR-21-5p might be a potential disease-modifying compound in OA, as it promotes hyaline cartilage production. These results provided that novel insights into the important function in OA pathological development.


Assuntos
Condrócitos/metabolismo , Interleucina-1beta/farmacologia , MicroRNAs/biossíntese , MicroRNAs/farmacologia , Osteoartrite/metabolismo , Adulto , Células Cultivadas , Condrócitos/efeitos dos fármacos , Condrócitos/patologia , Feminino , Humanos , Masculino , MicroRNAs/uso terapêutico , Pessoa de Meia-Idade , Osteoartrite/patologia , Osteoartrite/prevenção & controle
13.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(5): 540-546, 2019 May 30.
Artigo em Chinês | MEDLINE | ID: mdl-31140417

RESUMO

OBJECTIVE: To explore the pathogenesis of gastric cancer through a bioinformatic approach to provide evidence for the prevention and treatment of gastric cancer. METHODS: The differentially expressed genes (DEGs) in gastric cancer and normal gastric mucosa in GSE79973 dataset were analyzed using GEO2R online tool. GO analysis and KEGG pathway enrichment analysis of the DEGs in DAVID database were performed. The protein interaction network was constructed using STRING database, and the key genes (Hub genes) were screened and their functional modules were analyzed using Cytoscape software. The GEPIA database was used to validate the Hub genes, and the Target Scan database was used to predict the microRNAs that regulate the target genes; OncomiR was used to analyze the expressions of the microRNAs in gastric cancer tissues and their relationship with the survival outcomes of the patients. RESULTS: A total of 181 DEGs were identified in gastric cancer, and 10 hub genes were screened by the protein- protein interaction network. Functional analysis showed that these DEGs were involved mainly in protein digestion and absorption, PI3K-Akt signaling pathway, ECM-receptor interaction and platelet activation signal pathway. GEPIA database validation showed that COL1A1 was highly expressed in gastric cancer tissues and was associated with a poor prognosis of patients with gastric cancer. MiR-129-5p was found to bind to the 3'UTR of COL1A1 mRNA, and compared with that in normal tissues, miR-129-5p expression was obviously down-regulated in gastric cancer tissues, and was correlated with the prognosis of the patients. CONCLUSIONS: COL1A1 under regulation by MiR-129-5p is a potential therapeutic target for gastric cancer.


Assuntos
Colágeno Tipo I , Biologia Computacional , MicroRNAs , Neoplasias Gástricas , Colágeno Tipo I/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/uso terapêutico , Fosfatidilinositol 3-Quinases , Neoplasias Gástricas/tratamento farmacológico
14.
Chem Biol Interact ; 308: 206-215, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31136735

RESUMO

Oligonucleotide-based therapies are advanced novel interventions used in the management of various respiratory diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD). These agents primarily act by gene silencing or RNA interference. Better methodologies and techniques are the need of the hour that can deliver these agents to tissues and cells in a target specific manner by which their maximum potential can be reached in the management of chronic inflammatory diseases. Nanoparticles play an important role in the target-specific delivery of drugs. In addition, oligonucleotides also are extensively used for gene transfer in the form of polymeric, liposomal and inorganic carrier materials. Therefore, the current review focuses on various novel dosage forms like nanoparticles, liposomes that can be used efficiently for the delivery of various oligonucleotides such as siRNA and miRNA. We also discuss the future perspectives and targets for oligonucleotides in the management of respiratory diseases.


Assuntos
Portadores de Fármacos/química , Oligonucleotídeos Antissenso/uso terapêutico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Dendrímeros/química , Humanos , Lipossomos/química , MicroRNAs/química , MicroRNAs/uso terapêutico , Nanopartículas/química , Oligonucleotídeos Antissenso/química , Interferência de RNA , RNA Interferente Pequeno/química , RNA Interferente Pequeno/uso terapêutico
15.
Pancreatology ; 19(4): 557-565, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31122822

RESUMO

Acute pancreatitis (AP) is a type of sterile inflammation of the pancreas, potentially leading to systemic inflammatory response syndrome or multiple organ failure. An emerging evidence that dysfunction of miRNA expression may alter pivotal physiological functions and lead to inflammation infiltration and complication of multiple diseases, including AP. Here, the AP model was successfully replicated using cerulein in vitro and in vivo. RT-qPCR was used to detect low expression of miR-148a in AP. This study verified that IL-6 was a direct target of miR-148a. Over-expression of miR-148a decreased the mRNA and protein levels of IL-6 by RT-qPCR and Elisa. Moreover, over-expression of miR-148a improved the pathological state of AP through H&E and MPO staining and transmission electron microscopy. After over-expressing miR-148a, Western blot and immunohistochemical method were used to confirm the reduction of autophagosomes and autolysosomes, blockade of the levels of p-STAT3, LC3-II, ATG7, ATG4c, Beclin1 and the increased p62 expression in AP. The expression of LAMP-2 was not significantly different. In addition, IL-6 and AG490, the IL-6/STAT3 signaling inhibitor, were used to verify the role of IL-6/STAT3 signaling in the regulation of miR-148a on autophagy in cerulein-induced AP in vitro and in vivo. Taken together, our findings indicate that miR-148a suppresses autophagy via regulating IL-6/STAT3 signaling in cerulein-induced AP in vitro and in vivo. The miR-148a appears to be a promising candidate for the gene therapy of AP.


Assuntos
Autofagia/efeitos dos fármacos , Terapia Genética/métodos , Interleucina-6/biossíntese , MicroRNAs/uso terapêutico , Pancreatite/terapia , Fator de Transcrição STAT3/biossíntese , Transdução de Sinais/efeitos dos fármacos , Doença Aguda , Animais , Linhagem Celular , Ceruletídeo , Regulação para Baixo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Vetores Genéticos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pancreatite/induzido quimicamente , Pancreatite/patologia , Ratos , Fator de Transcrição STAT3/efeitos dos fármacos
16.
Biol Res ; 52(1): 24, 2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30995936

RESUMO

BACKGROUND: To analyze the relative expression of PELI3 and its mechanistic involvement in the non-small cell lung cancer (NSCLC). METHODS: PELI3 expression in NSCLC tissue samples was determined by the immunohistochemistry. The transcripts abundance of PELI3 was measured with real-time PCR. The protein intensity was analyzed by western blot. The overall survival in respect to PELI3 or miR-365a-5p expression was plotted by the Kaplan-Meier's analysis. Cell growth was determined by colony formation assay. Cell viability was measured by MTT assay. The migration and invasion were evaluated by wound healing and transwell assay respectively. The regulatory effect of miR-365a-5p on PELI3 was interrogated with luciferase reporter assay. The direct binding between miR-365a-5p and PELI3 was analyzed by pulldown assay. RESULTS: PELI3 was aberrantly up-regulated in NSCLC both in vivo and in vitro. High level of PELI3 associated with poor prognosis. PELI3-deficiency significantly inhibited cell viability, colony formation, migration and invasion. We further identified that miR-365a-5p negatively regulated PELI3 in this disease. Ectopic expression of miR-365a-5p in both A549 and H1299 phenocopied PELI3-deficiency. Meanwhile, PELI3-silencing significantly abolished the pro-tumoral effect elicited by miR-365a-5p inhibition. CONCLUSION: Our results highlighted the importance of dysregulated miR-365a-5p-PELI3 signaling axis in NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/metabolismo , Regulação para Baixo/fisiologia , Neoplasias Pulmonares/metabolismo , MicroRNAs/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Corantes , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , MicroRNAs/uso terapêutico , Sais de Tetrazólio , Tiazóis , Ubiquitina-Proteína Ligases/farmacologia
17.
Int J Mol Med ; 43(6): 2319-2328, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30942393

RESUMO

Exosomes serve important functions in cell­to­cell communication and biological functions by serving as a delivery cargo shuttle for various molecules. The application of an improved delivery method for microRNAs (miRNAs/miRs) may enhance their potential as a therapeutic tool in cardiac diseases. Thus, the present study investigated whether human peripheral blood­derived exosomes may be used as a delivery cargo system for miRNAs, and whether the delivery of miR­21 using a human peripheral blood derived­exosome may influence the degree of remodeling following myocardial infarction (MI). In H9C2 and HL­1 cells, miR­21 expression was successfully regulated by treatment with human peripheral blood derived­exosomes loaded with an miR­21 mimic or inhibitor compared with untreated cells. In addition, the mRNA and protein expression levels of SMAD family member 7 (Smad7), phosphatase and tensin homolog (PTEN) and matrix metalloproteinase 2 (MMP2), which are involved in cardiac fibrosis, were associated with the uptake of miR­21 mimic­ or inhibitor­loaded exosomes. Similarly, the in vivo mRNA and protein expression of Smad7, PTEN and MMP2 were altered following treatment with miR­21 mimic­ or inhibitor­loaded exosomes. Furthermore, miR­21 mimic­loaded exosomes enhanced fibrosis, whereas miR­21 inhibitor­loaded exosomes reduced fibrosis in a mouse MI model. These results suggested that miRNA­loaded human peripheral blood derived­exosomes may be used as a therapeutic tool for cardiac diseases.


Assuntos
Portadores de Fármacos/química , Exossomos/química , MicroRNAs/administração & dosagem , Infarto do Miocárdio/terapia , Idoso , Animais , Linhagem Celular , Feminino , Fibrose , Terapia Genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/uso terapêutico , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Miocárdio/patologia
18.
Vet Comp Oncol ; 17(3): 407-412, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31020761

RESUMO

MicroRNAs (miRNA) are small, noncoding RNA molecules consisting of 18 to 25 nucleotides. Malignant melanomas (MMs) are one of the most common malignancies in both dogs and humans. We previously reported that chemically modified synthetic miRNA-205 (miR-205BP/S3) inhibits melanoma growth in vitro and in vivo. The present study aimed to evaluate the efficacy of intratumoral administration of synthetic miR-205 for spontaneous CMMs and to evaluate its potential as systemic therapy. Ten dogs with various stages of MM were treated with miR-205BP/S3 injected into tumours. Adverse effects (AEs) were assessed in accordance with the Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE) v1.1 guidelines. Five cases attained complete remission (CR), three attained stable disease (SD), and two cases displayed characteristics of progressive disease (PD). In all cases, no changes were observed in the blood parameters upon miRNA administration, and miR-205BP/S3 administration did not yield any side effects. The present results suggest that intratumoral administration of miR-205BP/S3 is a potentially applicable treatment for canine melanoma.


Assuntos
Doenças do Cão/terapia , Melanoma/veterinária , MicroRNAs/uso terapêutico , Animais , Cães , Feminino , Injeções/métodos , Injeções/veterinária , Masculino , Melanoma/terapia , MicroRNAs/efeitos adversos , MicroRNAs/síntese química
19.
Int Urol Nephrol ; 51(5): 889-896, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30888602

RESUMO

Peritoneal fibrosis is recognised as the main cause of the technical failure of peritoneal dialysis (PD), and currently, there are no specific and effective anti-fibrosis therapies. We have found that miR-200a is down-regulated in a rat model of PD-related peritoneal fibrosis (PF) and could inhibit transforming growth factor beta 1 (TGF-ß1)-induced epithelial-mesenchymal transition (EMT) in peritoneal mesothelial cells by target ZEB1/2. However, its treatment role in vivo is still largely unclear. In this study, we examined the therapeutic potential for miR-200a on PD-related PF in a rat model of PD induced by daily infusion of 4.25% dextrose-containing dialysate. Male Sprague-Dawley rats were divided into four groups: control group, PD group, PD + miR-agomir-NC group, and PD + miR-200a-agomir group (n = 5 in each group). MiR-200a agomir was delivered into the peritoneum by intra-peritoneal injection on days 10 and 20 after PD. We found that treatment with miR-200a agomir significantly reduced the collagen volume fraction (CVF) of the peritoneum and prevented peritoneal dysfunction. The up-regulation of the EMT marker (decreased E-cadherin and increased α-smooth muscle actin) and extracellular matrix (fibronectin and collagen I) was significantly ameliorated by miR-200a in the PD + miR-200a-agomir group. Furthermore, we demonstrated that miR-200a inhibition of PF in vivo was associated with the suppression of ZEB1 and 2, which were proved to be the target of miR-200a in our previous study. In conclusion, results from the present study suggest that treatment with miR-200a may represent a novel and effective therapy for PD-related PF.


Assuntos
MicroRNAs/uso terapêutico , Diálise Peritoneal , Fibrose Peritoneal/terapia , Animais , Modelos Animais de Doenças , Masculino , Diálise Peritoneal/efeitos adversos , Fibrose Peritoneal/etiologia , Fibrose Peritoneal/fisiopatologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
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