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1.
Med Hypotheses ; 143: 110203, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33017912

RESUMO

MicroRNAs (miRNAs) naturally occur in plants and all living organisms. They play an important role in gene regulation through binding toa specific region in open reading frames (ORFs) and/or untranslated regions (UTRs) to block the translation processes through either degrading or blocking mRNA resulting in knocking down or suppression of targeted genes. Plants and many organisms protect themselves from viruses through the production of miRNAs, which are complementary to 3UTR of viruses resulting in degrading the viral mRNA or block the translation on ribosomes. As pandemic, COVID-19, and its consequences on the global economy, we hypothesized a new approach for the treatment of COVID-19 paints. This approach includes designing a mix of miRNAs targeting several regions on COVID-19 open reading frame (ORF) and 3 UTR and suitable delivery system targeting respiratory system tissues. These synthesized miRNAs may be delivered to humansinnon-viral delivery systems such as liposomes like exosome (extracellular vesicle), polymer-based carriers, or inorganic nanoparticles, which are considered to be more suitable for human use.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/terapia , MicroRNAs/uso terapêutico , Pneumonia Viral/terapia , Regiões 3' não Traduzidas , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Sistemas de Liberação de Medicamentos , Exossomos , Regulação da Expressão Gênica , Técnicas de Transferência de Genes , Genoma Viral , Humanos , Lipossomos/química , Nanopartículas/química , Fases de Leitura Aberta , Pandemias , Pneumonia Viral/virologia , Polímeros/química
2.
Pharmacol Rev ; 72(4): 862-898, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32929000

RESUMO

RNA-based therapies, including RNA molecules as drugs and RNA-targeted small molecules, offer unique opportunities to expand the range of therapeutic targets. Various forms of RNAs may be used to selectively act on proteins, transcripts, and genes that cannot be targeted by conventional small molecules or proteins. Although development of RNA drugs faces unparalleled challenges, many strategies have been developed to improve RNA metabolic stability and intracellular delivery. A number of RNA drugs have been approved for medical use, including aptamers (e.g., pegaptanib) that mechanistically act on protein target and small interfering RNAs (e.g., patisiran and givosiran) and antisense oligonucleotides (e.g., inotersen and golodirsen) that directly interfere with RNA targets. Furthermore, guide RNAs are essential components of novel gene editing modalities, and mRNA therapeutics are under development for protein replacement therapy or vaccination, including those against unprecedented severe acute respiratory syndrome coronavirus pandemic. Moreover, functional RNAs or RNA motifs are highly structured to form binding pockets or clefts that are accessible by small molecules. Many natural, semisynthetic, or synthetic antibiotics (e.g., aminoglycosides, tetracyclines, macrolides, oxazolidinones, and phenicols) can directly bind to ribosomal RNAs to achieve the inhibition of bacterial infections. Therefore, there is growing interest in developing RNA-targeted small-molecule drugs amenable to oral administration, and some (e.g., risdiplam and branaplam) have entered clinical trials. Here, we review the pharmacology of novel RNA drugs and RNA-targeted small-molecule medications, with a focus on recent progresses and strategies. Challenges in the development of novel druggable RNA entities and identification of viable RNA targets and selective small-molecule binders are discussed. SIGNIFICANCE STATEMENT: With the understanding of RNA functions and critical roles in diseases, as well as the development of RNA-related technologies, there is growing interest in developing novel RNA-based therapeutics. This comprehensive review presents pharmacology of both RNA drugs and RNA-targeted small-molecule medications, focusing on novel mechanisms of action, the most recent progress, and existing challenges.


Assuntos
RNA/efeitos dos fármacos , RNA/farmacologia , Aptâmeros de Nucleotídeos/farmacologia , Aptâmeros de Nucleotídeos/uso terapêutico , Betacoronavirus , Técnicas de Química Analítica/métodos , Técnicas de Química Analítica/normas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Infecções por Coronavirus/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Desenvolvimento de Medicamentos/organização & administração , Descoberta de Drogas , Humanos , MicroRNAs/farmacologia , MicroRNAs/uso terapêutico , Oligonucleotídeos Antissenso/farmacologia , Oligonucleotídeos Antissenso/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , RNA/efeitos adversos , RNA Antissenso/farmacologia , RNA Antissenso/uso terapêutico , RNA Guia/farmacologia , RNA Guia/uso terapêutico , RNA Mensageiro/efeitos dos fármacos , RNA Mensageiro/farmacologia , RNA Ribossômico/efeitos dos fármacos , RNA Ribossômico/farmacologia , RNA Interferente Pequeno/farmacologia , RNA Interferente Pequeno/uso terapêutico , RNA Viral/efeitos dos fármacos , Ribonucleases/metabolismo , Riboswitch/efeitos dos fármacos
3.
Nucleic Acids Res ; 48(14): 7623-7639, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32644123

RESUMO

RNA therapeutics are a promising strategy to treat genetic diseases caused by the overexpression or aberrant splicing of a specific protein. The field has seen major strides in the clinical efficacy of this class of molecules, largely due to chemical modifications and delivery strategies that improve nuclease resistance and enhance cell penetration. However, a major obstacle in the development of RNA therapeutics continues to be the imprecise, difficult, and often problematic nature of most methods used to measure cell penetration. Here, we review these methods and clearly distinguish between those that measure total cellular uptake of RNA therapeutics, which includes both productive and non-productive uptake, and those that measure cytosolic/nuclear penetration, which represents only productive uptake. We critically analyze the benefits and drawbacks of each method. Finally, we use key examples to illustrate how, despite rigorous experimentation and proper controls, our understanding of the mechanism of gymnotic uptake of RNA therapeutics remains limited by the methods commonly used to analyze RNA delivery.


Assuntos
RNA/metabolismo , RNA/uso terapêutico , Aptâmeros de Nucleotídeos/uso terapêutico , Núcleo Celular/metabolismo , Citosol/metabolismo , Doenças Genéticas Inatas/tratamento farmacológico , Técnicas Genéticas , Humanos , MicroRNAs/uso terapêutico , Microscopia Eletrônica , Oligonucleotídeos Antissenso/uso terapêutico , RNA/química , RNA/farmacocinética , RNA Interferente Pequeno/uso terapêutico , Espectrometria de Fluorescência
4.
N Engl J Med ; 383(2): 151-158, 2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640133

RESUMO

Two patients with familial amyotrophic lateral sclerosis (ALS) and mutations in the gene encoding superoxide dismutase 1 (SOD1) were treated with a single intrathecal infusion of adeno-associated virus encoding a microRNA targeting SOD1. In Patient 1, SOD1 levels in spinal cord tissue as analyzed on autopsy were lower than corresponding levels in untreated patients with SOD1-mediated ALS and in healthy controls. Levels of SOD1 in cerebrospinal fluid were transiently and only slightly lower in Patient 1 but were not affected in Patient 2. In Patient 1, meningoradiculitis developed after the infusion; Patient 2 was pretreated with immunosuppressive drugs and did not have this complication. Patient 1 had transient improvement in the strength of his right leg, a measure that had been relatively stable throughout his disease course, but there was no change in his vital capacity. Patient 2 had stable scores on a composite measure of ALS function and a stable vital capacity during a 12-month period. This study showed that intrathecal microRNA can be used as a potential treatment for SOD1-mediated ALS.


Assuntos
Esclerose Amiotrófica Lateral/terapia , MicroRNAs/uso terapêutico , Superóxido Dismutase-1/líquido cefalorraquidiano , Esclerose Amiotrófica Lateral/líquido cefalorraquidiano , Esclerose Amiotrófica Lateral/genética , Dependovirus , Evolução Fatal , Inativação Gênica , Terapia Genética , Vetores Genéticos , Humanos , Injeções Espinhais , Masculino , Meningoencefalite , Pessoa de Meia-Idade , Mutação , Estudo de Prova de Conceito , Medula Espinal/química , Medula Espinal/patologia , Superóxido Dismutase-1/análise , Superóxido Dismutase-1/genética , Capacidade Vital , Adulto Jovem
6.
Nat Rev Cardiol ; 17(11): 685-697, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32483304

RESUMO

Extracellular vesicles (EVs) are a heterogeneous group of natural particles that are relevant to the treatment of cardiovascular diseases. These endogenous vesicles have certain properties that allow them to survive in the extracellular space, bypass biological barriers and deliver their biologically active molecular cargo to recipient cells. Moreover, EVs can be bioengineered to increase their stability, bioactivity, presentation to acceptor cells and capacity for on-target binding at both cell-type-specific and tissue-specific levels. Bioengineering of EVs involves the modification of the donor cell before EV isolation or direct modification of the EV properties after isolation. The therapeutic potential of native EVs and bioengineered EVs has been only minimally explored in the context of cardiovascular diseases. Efforts to harness the therapeutic potential of EVs will require innovative approaches and a comprehensive integration of knowledge gathered from decades of research into molecular-compound delivery. In this Review, we outline the endogenous properties of EVs that make them natural delivery agents as well as the features that can be improved by bioengineering. We also discuss the therapeutic applications of native and bioengineered EVs to cardiovascular diseases and examine the opportunities and challenges that need to be addressed to advance this research area, with an emphasis on clinical translation.


Assuntos
Bioengenharia , Doenças Cardiovasculares/terapia , Vesículas Extracelulares/transplante , Isquemia/terapia , Infarto do Miocárdio/terapia , Regeneração , Células-Tronco/metabolismo , Acidente Vascular Cerebral/terapia , Encéfalo/fisiologia , Sobrevivência Celular , Vesículas Extracelulares/metabolismo , Extremidades/irrigação sanguínea , Coração/fisiologia , Humanos , MicroRNAs/metabolismo , MicroRNAs/uso terapêutico , Miócitos Cardíacos , Comunicação Parácrina
8.
Curr Pharm Biotechnol ; 21(12): 1186-1203, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32310047

RESUMO

MicroRNAs (miRNA) are small non-coding RNAs that act as one of the main regulators of gene expression. They are involved in maintaining a proper balance of diverse processes, including differentiation, proliferation, and cell death in normal cells. Cancer biology can also be affected by these molecules by modulating the expression of oncogenes or tumor suppressor genes. Thus, miRNA based anticancer therapy is currently being developed either alone or in combination with chemotherapy agents used in cancer management, aiming at promoting tumor regression and increasing cure rate. Access to large quantities of RNA agents can facilitate RNA research and development. In addition to currently used in vitro methods, fermentation-based approaches have recently been developed, which can cost-effectively produce biological RNA agents with proper folding needed for the development of RNA-based therapeutics. Nevertheless, a major challenge in translating preclinical studies to clinical for miRNA-based cancer therapy is the efficient delivery of these agents to target cells. Targeting miRNAs/anti-miRNAs using antibodies and/or peptides can minimize cellular and systemic toxicity. Here, we provide a brief review of miRNA in the following aspects: biogenesis and mechanism of action of miRNAs, the role of miRNAs in cancer as tumor suppressors or oncogenes, the potential of using miRNAs as novel and promising therapeutics, miRNA-mediated chemo-sensitization, and currently utilized methods for the in vitro and in vivo production of RNA agents. Finally, an update on the viral and non-viral delivery systems is addressed.


Assuntos
Regulação Neoplásica da Expressão Gênica , Terapia Genética/métodos , MicroRNAs/uso terapêutico , Neoplasias/terapia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Técnicas de Transferência de Genes , Genes Supressores de Tumor , Humanos , MicroRNAs/genética , Mimetismo Molecular , Neoplasias/genética , Neoplasias/patologia , Oncogenes
9.
Nat Commun ; 11(1): 1185, 2020 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-32132543

RESUMO

Pulmonary arterial hypertension (PAH) is a severe disorder of lung vasculature that causes right heart failure. Homoeostatic effects of flow-activated transcription factor Krüppel-like factor 2 (KLF2) are compromised in PAH. Here, we show that KLF2-induced exosomal microRNAs, miR-181a-5p and miR-324-5p act together to attenuate pulmonary vascular remodelling and that their actions are mediated by Notch4 and ETS1 and other key regulators of vascular homoeostasis. Expressions of KLF2, miR-181a-5p and miR-324-5p are reduced, while levels of their target genes are elevated in pre-clinical PAH, idiopathic PAH and heritable PAH with missense p.H288Y KLF2 mutation. Therapeutic supplementation of miR-181a-5p and miR-324-5p reduces proliferative and angiogenic responses in patient-derived cells and attenuates disease progression in PAH mice. This study shows that reduced KLF2 signalling is a common feature of human PAH and highlights the potential therapeutic role of KLF2-regulated exosomal miRNAs in PAH and other diseases associated with vascular remodelling.


Assuntos
Terapia Genética/métodos , Fatores de Transcrição Kruppel-Like/metabolismo , MicroRNAs/uso terapêutico , Hipertensão Arterial Pulmonar/terapia , Adulto , Idoso , Animais , Proliferação de Células/genética , Modelos Animais de Doenças , Progressão da Doença , Células Endoteliais , Exossomos/genética , Exossomos/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Fatores de Transcrição Kruppel-Like/genética , Pulmão/irrigação sanguínea , Pulmão/citologia , Pulmão/patologia , Masculino , Camundongos , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Cultura Primária de Células , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/patologia , Artéria Pulmonar/citologia , Artéria Pulmonar/patologia , Transdução de Sinais/genética , Remodelação Vascular/genética , Adulto Jovem
10.
Curr Atheroscler Rep ; 22(2): 10, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034521

RESUMO

PURPOSE OF REVIEW: Atherosclerosis is characterized by accumulation of lipids and chronic inflammation in medium size to large arteries. Recently, RNA-based antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are being developed, along with small molecule-based drugs and monoclonal antibodies, for the treatment of risk factors associated with atherosclerosis.. The purpose of this review is to describe nucleic acid-based therapeutics and introduce novel RNAs that might become future tools for treatment of atherosclerosis. RECENT FINDINGS: RNA-based inhibitors for PCSK9, Lp(a), ApoCIII, and ANGPTL3 have been successfully tested in phase II-III clinical trials. Moreover, multiple microRNA and long non-coding RNAs have been found to reduce atherogenesis in preclinical animal models. Clinical trials especially with ASOs and siRNAs directed to liver, targeting cholesterol and lipoprotein metabolism, have shown promising results. Additional research in larger patient cohorts is needed to fully evaluate the therapeutic potential of these new drugs.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , MicroRNAs/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico , RNA Longo não Codificante/uso terapêutico , RNA Interferente Pequeno/uso terapêutico , Proteínas Semelhantes a Angiopoietina/antagonistas & inibidores , Animais , Apolipoproteína C-III/antagonistas & inibidores , Aterosclerose/metabolismo , Humanos , Lipoproteína(a)/antagonistas & inibidores , Lipoproteína(a)/metabolismo , Fígado/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Pró-Proteína Convertase 9/antagonistas & inibidores , RNA Interferente Pequeno/farmacologia
11.
Int J Mol Sci ; 21(3)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973111

RESUMO

The interest in non-coding RNAs, which started more than a decade ago, has still not weakened. A wealth of experimental and clinical studies has suggested the potential of non-coding RNAs, especially the short-sized microRNAs (miRs), to be used as the new generation of therapeutic targets and biomarkers of cardiovascular disease, an ever-growing public health issue in the modern world. Among the hundreds of miRs characterized so far, microRNA-1 (miR-1) and microRNA-21 (miR-21) have received some attention and have been associated with cardiac injury and cardioprotection. In this review article, we summarize the current knowledge of the function of these two miRs in the heart, their association with cardiac injury, and their potential cardioprotective roles and biomarker value. While this field has already been extensively studied, much remains to be done before research findings can be translated into clinical application for patient's benefit.


Assuntos
Cardiotônicos/uso terapêutico , Cardiopatias/tratamento farmacológico , MicroRNAs/uso terapêutico , Animais , Antineoplásicos/toxicidade , Arritmias Cardíacas/tratamento farmacológico , Biomarcadores , Cardiomiopatias/tratamento farmacológico , Cardiotoxinas , Doenças Cardiovasculares/tratamento farmacológico , Coração , Cardiopatias/induzido quimicamente , Traumatismos Cardíacos/induzido quimicamente , Traumatismos Cardíacos/tratamento farmacológico , Humanos , Radioterapia/efeitos adversos
12.
J Biomed Sci ; 27(1): 4, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31898495

RESUMO

Dengue virus (DENV) is the etiological agent of dengue fever. Severe dengue could be fatal and there is currently no effective antiviral agent or vaccine. The only licensed vaccine, Dengvaxia, has low efficacy against serotypes 1 and 2. Cellular miRNAs are post-transcriptional regulators that could play a role in direct regulation of viral genes. Host miRNA expressions could either promote or repress viral replications. Induction of some cellular miRNAs could help the virus to evade the host immune response by suppressing the IFN-α/ß signaling pathway while others could upregulate IFN-α/ß production and inhibit the viral infection. Understanding miRNA expressions and functions during dengue infections would provide insights into the development of miRNA-based therapeutics which could be strategized to act either as miRNA antagonists or miRNA mimics. The known mechanisms of how miRNAs impact DENV replication are diverse. They could suppress DENV multiplication by directly binding to the viral genome, resulting in translational repression. Other miRNA actions include modulation of host factors. In addition, miRNAs that could modulate immunopathogenesis are discussed. Major hurdles lie in the development of chemical modifications and delivery systems for in vivo delivery. Nevertheless, advancement in miRNA formulations and delivery systems hold great promise for the therapeutic potential of miRNA-based therapy, as supported by Miravirsen for treatment of Hepatitis C infection which has successfully completed phase II clinical trial.


Assuntos
Dengue/tratamento farmacológico , Interferon-alfa/genética , Interferon beta/genética , MicroRNAs/genética , Antivirais , Dengue/genética , Dengue/virologia , Vírus da Dengue/genética , Vírus da Dengue/patogenicidade , Humanos , Imunidade Inata/genética , Interferon-alfa/uso terapêutico , Interferon beta/uso terapêutico , MicroRNAs/uso terapêutico , Transdução de Sinais/genética , Replicação Viral/genética
13.
Arch Gynecol Obstet ; 301(3): 707-714, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31903498

RESUMO

PURPOSE: Recent studies have demonstrated the differential expression of micro(mi)RNAs in endometriosis. Previously, we reported the low expression of miR-141 in patients with this disease. Epithelial-to-mesenchymal transition (EMT) and the transforming growth factor-beta1 (TGF-ß1)-induced SMAD2 signalling pathway are central to tumour proliferation and invasion. However, the role of miR-141 in regulating the TGF-ß1/SMAD2 signalling pathway and the associated EMT to be elucidated. METHODS: The levels of TGF-ß1/SMAD2 signalling and EMT markers expression in eutopic and ectopic endometria of endometriosis were determined by immunohistochemistry and western blot analyses. MiR-141 expression was analysed by quantitative reverse-transcription polymerase chain reaction. Cellular invasion and proliferation were determined by transwell and CCK-8 assays, respectively. Functional assay of miR-141 was performed using plasmid and shRNA transfection methods. RESULT: The presence of miR-141, EMT, and TGF-ß1/SMAD2 signalling markers were detected in eutopic and ectopic endometria of endometriosis. TGF-ß1-induced EMT in Ishikawa (ISK) cells by activating the SMAD2 signalling pathway, whereas miR-141 inhibited the TGF-ß1-induced EMT, proliferation and invasion abilities of these cells. CONCLUSION: These data identify miR-141 as a novel driver of EMT in endometriosis, implicates the link between miR-141 and TGF-ß1/SMAD2 signalling pathway in the context of endometriosis, and underscore the role of EMT in the development of endometriosis.


Assuntos
Endometriose/genética , Transição Epitelial-Mesenquimal/genética , MicroRNAs/uso terapêutico , Fator de Crescimento Transformador beta1/efeitos dos fármacos , Endometriose/patologia , Feminino , Humanos , MicroRNAs/farmacologia , Transdução de Sinais , Transfecção
14.
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
15.
Cell Mol Life Sci ; 77(6): 1059-1086, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31637450

RESUMO

Concomitant with advances in research regarding the role of miRNAs in sustaining carcinogenesis, major concerns about their delivery options for anticancer therapies have been raised. The answer to this problem may come from the world of nanoparticles such as liposomes, exosomes, polymers, dendrimers, mesoporous silica nanoparticles, quantum dots and metal-based nanoparticles which have been proved as versatile and valuable vehicles for many biomolecules including miRNAs. In another train of thoughts, the general scheme of miRNA modulation consists in inhibition of oncomiRNA expression and restoration of tumor suppressor ones. The codelivery of two miRNAs or miRNAs in combination with chemotherapeutics or small molecules was also proposed. The present review presents the latest advancements in miRNA delivery based on nanoparticle-related strategies.


Assuntos
MicroRNAs/administração & dosagem , Neoplasias/terapia , Animais , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Técnicas de Transferência de Genes , Terapia Genética/métodos , Humanos , MicroRNAs/genética , MicroRNAs/farmacocinética , MicroRNAs/uso terapêutico , Nanomedicina/métodos , Nanopartículas/química , Neoplasias/genética
16.
Mycoses ; 63(1): 4-20, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31597205

RESUMO

Due to their physiological and biological characteristics, numerous fungi are potentially emerging pathogens. Active dynamicity of fungal pathogens causes life-threatening infections annually impose high costs to the health systems. Although immune responses play crucial roles in controlling the fate of fungal infections, immunocompromised patients are at high risk with high mortality. Tuning the immune response against fungal infections might be an effective strategy for controlling and reducing the pathological damages. MicroRNAs (miRNAs) are known as the master regulators of immune response. These single-stranded tuners (18-23 bp non-coding RNAs) are endogenously expressed by all metazoan eukaryotes and have emerged as the master gene expression controllers of at least 30% human genes. In this review article, following the review of biology and physiology (biogenesis and mechanism of actions) of miRNAs and immune response against fungal infections, the interactions between them were scrutinised. In conclusion, miRNAs might be considered as one of the potential goals in immunotherapy for fungal infections. Undoubtedly, advanced studies in this field, further identifying of miRNA roles in governing the immune response, pave the way for inclusion of miRNA-related immunotherapeutic in the treatment of life-threatening fungal infections.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , MicroRNAs , Micoses , Infecções Oportunistas Relacionadas com a AIDS/imunologia , Infecções Oportunistas Relacionadas com a AIDS/microbiologia , Infecções Oportunistas Relacionadas com a AIDS/terapia , Animais , Aspergilose/imunologia , Aspergilose/metabolismo , Candidíase/imunologia , Candidíase/metabolismo , Coinfecção/imunologia , Coinfecção/metabolismo , Coinfecção/microbiologia , Criptococose/imunologia , Criptococose/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Imunoterapia , MicroRNAs/biossíntese , MicroRNAs/imunologia , MicroRNAs/metabolismo , MicroRNAs/uso terapêutico , Micoses/imunologia , Micoses/terapia , Paracoccidioidomicose/imunologia , Paracoccidioidomicose/metabolismo , Transdução de Sinais/genética
17.
Nat Biomed Eng ; 4(1): 69-83, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31844155

RESUMO

Exosomes are attractive as nucleic-acid carriers because of their favourable pharmacokinetic and immunological properties and their ability to penetrate physiological barriers that are impermeable to synthetic drug-delivery vehicles. However, inserting exogenous nucleic acids, especially large messenger RNAs, into cell-secreted exosomes leads to low yields. Here we report a cellular-nanoporation method for the production of large quantities of exosomes containing therapeutic mRNAs and targeting peptides. We transfected various source cells with plasmid DNAs and stimulated the cells with a focal and transient electrical stimulus that promotes the release of exosomes carrying transcribed mRNAs and targeting peptides. Compared with bulk electroporation and other exosome-production strategies, cellular nanoporation produced up to 50-fold more exosomes and a more than 103-fold increase in exosomal mRNA transcripts, even from cells with low basal levels of exosome secretion. In orthotopic phosphatase and tensin homologue (PTEN)-deficient glioma mouse models, mRNA-containing exosomes restored tumour-suppressor function, enhanced inhibition of tumour growth and increased survival. Cellular nanoporation may enable the use of exosomes as a universal nucleic-acid carrier for applications requiring transcriptional manipulation.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Eletroporação/métodos , Exossomos/metabolismo , Glioma/tratamento farmacológico , RNA Mensageiro/uso terapêutico , Animais , Células Cultivadas , Modelos Animais de Doenças , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , MicroRNAs/uso terapêutico , Nanotecnologia , RNA Mensageiro/metabolismo , Transdução de Sinais
18.
Toxicol Appl Pharmacol ; 386: 114827, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31734320

RESUMO

Endothelial-mesenchymal transition (EndMT) is a frequent event in endothelial dysfunction, which is associated with pulmonary arterial hypertension (PAH). MiR-181 family members exert diverse effects in multiple biological processes. However, the relationships between miR-181b-5p (miR-181b) and EndMT in PAH are not well understood. In this study, Sprague-Dawley (SD) rats were injected with monocrotaline (MCT) to establish PAH model, and primary rat pulmonary arterial endothelial cells (rPAECs) were treated with TNF-α, TGFß1 and IL-1ß in combination to induce EndMT (I-EndMT). Then we explored miR-181b expression and examined its functional role in PAH. Our data showed that miR-181b was down-expressed in PAH, and its overexpression attenuated the hemodynamics, pulmonary vascular hypertrophy, right ventricular remodeling and EndMT process in MCT-induced PAH rats. In I-EndMT rPAECs, we observed that inducing miR-181b reversed the decrease of endothelial markers and increase of mesenchymal markers. However, knockdown of miR-181b induced similar effects to EndMT. In addition, endocan and TGFBR1 levels were also increased in EndMT, which were negatively regulated by miR-181b. Luciferase activity results indicated that endocan and TGFBR1 were direct target genes of miR-181b. In summary, our findings firstly demonstrate that the beneficial effect of miR-181b on PAH may be associated with endocan/TGFBR1-mediated EndMT, providing a new insight into the diagnosis and treatment of PAH.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , MicroRNAs/uso terapêutico , Monocrotalina/farmacologia , Proteoglicanas/antagonistas & inibidores , Hipertensão Arterial Pulmonar/tratamento farmacológico , Receptor do Fator de Crescimento Transformador beta Tipo I/antagonistas & inibidores , Animais , Células Cultivadas , Imunofluorescência , Masculino , MicroRNAs/farmacologia , Hipertensão Arterial Pulmonar/induzido quimicamente , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Ratos , Ratos Sprague-Dawley
19.
Cell Host Microbe ; 26(6): 779-794.e8, 2019 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-31784260

RESUMO

Fecal transfer from healthy donors is being explored as a microbiome modality. MicroRNAs (miRNAs) have been found to affect the microbiome. Multiple sclerosis (MS) patients have been shown to have an altered gut microbiome. Here, we unexpectedly found that transfer of feces harvested at peak disease from the experimental autoimmune encephalomyelitis (EAE) model of MS ameliorates disease in recipients in a miRNA-dependent manner. Specifically, we show that miR-30d is enriched in the feces of peak EAE and untreated MS patients. Synthetic miR-30d given orally ameliorates EAE through expansion of regulatory T cells (Tregs). Mechanistically, miR-30d regulates the expression of a lactase in Akkermansia muciniphila, which increases Akkermansia abundance in the gut. The expanded Akkermansia in turn increases Tregs to suppress EAE symptoms. Our findings report the mechanistic underpinnings of a miRNA-microbiome axis and suggest that the feces of diseased subjects might be enriched with miRNAs with therapeutic properties.


Assuntos
Encefalomielite Autoimune Experimental , Transplante de Microbiota Fecal , MicroRNAs/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Verrucomicrobia , Administração Oral , Animais , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/imunologia , Fezes , Microbioma Gastrointestinal/imunologia , Interações entre Hospedeiro e Microrganismos , Humanos , Lactase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Linfócitos T Reguladores/metabolismo , Verrucomicrobia/crescimento & desenvolvimento , Verrucomicrobia/imunologia , Verrucomicrobia/metabolismo
20.
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
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