RESUMO
BACKGROUND: miRNA therapeutics have gained attention during the past decade. These oligonucleotide treatments can modulate the expression of miRNAs in vivo and could be used to correct the imbalance of gene expression found in human diseases such as obesity, metabolic syndrome, and atherosclerosis. The in vivo efficacy of current anti-miRNA technologies hindered by physiological and cellular barriers to delivery into targeted cells and the nature of miRNAs that allows one to target an entire pathway that may lead to deleterious off-target effects. For these reasons, novel targeted delivery systems to inhibit miRNAs in specific tissues will be important for developing effective therapeutic strategies for numerous diseases including atherosclerosis. METHODS: We used pH low-insertion peptide (pHLIP) constructs as vehicles to deliver microRNA-33-5p (miR-33) antisense oligonucleotides to atherosclerotic plaques. Immunohistochemistry and histology analysis was performed to assess the efficacy of miR-33 silencing in atherosclerotic lesions. We also assessed how miR-33 inhibition affects gene expression in monocytes/macrophages by single-cell RNA transcriptomics. RESULTS: The anti-miR-33 conjugated pHLIP constructs are preferentially delivered to atherosclerotic plaque macrophages. The inhibition of miR-33 using pHLIP-directed macrophage targeting improves atherosclerosis regression by increasing collagen content and decreased lipid accumulation within vascular lesions. Single-cell RNA sequencing analysis revealed higher expression of fibrotic genes (Col2a1, Col3a1, Col1a2, Fn1, etc) and tissue inhibitor of metalloproteinase 3 (Timp3) and downregulation of Mmp12 in macrophages from atherosclerotic lesions targeted by pHLIP-anti-miR-33. CONCLUSIONS: This study provides proof of principle for the application of pHLIP for treating advanced atherosclerosis via pharmacological inhibition of miR-33 in macrophages that avoid the deleterious effects in other metabolic tissues. This may open new therapeutic opportunities for atherosclerosis-associated cardiovascular diseases via selective delivery of other protective miRNAs.
Assuntos
Aterosclerose , MicroRNAs , Placa Aterosclerótica , Antagomirs/metabolismo , Antagomirs/uso terapêutico , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/terapia , Humanos , Macrófagos/metabolismo , MicroRNAs/metabolismo , Placa Aterosclerótica/patologiaRESUMO
The discovery of the link between microRNAs (miRNAs) and a myriad of human diseases, particularly various cancer types, has generated significant interest in exploring their potential as a novel class of drugs. This has led to substantial investments in interdisciplinary research fields such as biology, chemistry, and medical science for the development of miRNA-based therapies. Furthermore, the recent global success of SARS-CoV-2 mRNA vaccines against the COVID-19 pandemic has further revitalized interest in RNA-based immunotherapies, including miRNA-based approaches to cancer treatment. Consequently, RNA therapeutics have emerged as highly adaptable and modular options for cancer therapy. Moreover, advancements in RNA chemistry and delivery methods have been pivotal in shaping the landscape of RNA-based immunotherapy, including miRNA-based approaches. Consequently, the biotechnology and pharmaceutical industry has witnessed a resurgence of interest in incorporating RNA-based immunotherapies and miRNA therapeutics into their development programs. Despite substantial progress in preclinical research, the field of miRNA-based therapeutics remains in its early stages, with only a few progressing to clinical development, none reaching phase III clinical trials or being approved by the US Food and Drug Administration (FDA), and several facing termination due to toxicity issues. These setbacks highlight existing challenges that must be addressed for the broad clinical application of miRNA-based therapeutics. Key challenges include establishing miRNA sensitivity, specificity, and selectivity towards their intended targets, mitigating immunogenic reactions and off-target effects, developing enhanced methods for targeted delivery, and determining optimal dosing for therapeutic efficacy while minimizing side effects. Additionally, the limited understanding of the precise functions of miRNAs limits their clinical utilization. Moreover, for miRNAs to be viable for cancer treatment, they must be technically and economically feasible for the widespread adoption of RNA therapies. As a result, a thorough risk evaluation of miRNA therapeutics is crucial to minimize off-target effects, prevent overdosing, and address various other issues. Nevertheless, the therapeutic potential of miRNAs for various diseases is evident, and future investigations are essential to determine their applicability in clinical settings.
Assuntos
MicroRNAs , Neoplasias , Humanos , MicroRNAs/genética , MicroRNAs/uso terapêutico , Pandemias , Neoplasias/genética , Neoplasias/terapia , ImunoterapiaRESUMO
An emerging but less explored shared pathophysiology across microbiota-gut-brain axis disorders is aberrant miRNA expression, which may represent novel therapeutic targets. miRNAs are small, endogenous non-coding RNAs that are important transcriptional repressors of gene expression. Most importantly, they regulate the integrity of the intestinal epithelial and blood-brain barriers and serve as an important communication channel between the gut microbiome and the host. A well-defined understanding of the mode of action, therapeutic strategies and delivery mechanisms of miRNAs is pivotal in translating the clinical applications of miRNA-based therapeutics. Accumulating evidence links disorders of the microbiota-gut-brain axis with a compromised gut-blood-brain-barrier, causing gut contents such as immune cells and microbiota to enter the bloodstream leading to low-grade systemic inflammation. This has the potential to affect all organs, including the brain, causing central inflammation and the development of neurodegenerative and neuropsychiatric diseases. In this review, we have examined in detail miRNA biogenesis, strategies for therapeutic application, delivery mechanisms, as well as their pathophysiology and clinical applications in inflammatory gut-brain disorders. The research data in this review was drawn from the following databases: PubMed, Google Scholar, and Clinicaltrials.gov. With increasing evidence of the pathophysiological importance for miRNAs in microbiota-gut-brain axis disorders, therapeutic targeting of cross-regulated miRNAs in these disorders displays potentially transformative and translational potential. Further preclinical research and human clinical trials are required to further advance this area of research.
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Encefalopatias , Microbioma Gastrointestinal , MicroRNAs , Humanos , Eixo Encéfalo-Intestino , MicroRNAs/genética , Microbioma Gastrointestinal/fisiologia , Encéfalo , Inflamação/genéticaRESUMO
Breast cancer exhibits various epigenetic abnormalities that regulate gene expression and contribute to tumor characteristics. Epigenetic alterations play a significant role in cancer development and progression, and epigenetic-targeting drugs such as DNA methyltransferase inhibitors, histone-modifying enzymes, and mRNA regulators (such as miRNA mimics and antagomiRs) can reverse these alterations. Therefore, these epigenetic-targeting drugs are promising candidates for cancer treatment. However, there is currently no effective epi-drug monotherapy for breast cancer. Combining epigenetic drugs with conventional therapies has yielded positive outcomes and may be a promising strategy for breast cancer therapy. DNA methyltransferase inhibitors, such as azacitidine, and histone deacetylase inhibitors, such as vorinostat, have been used in combination with chemotherapy to treat breast cancer. miRNA regulators, such as miRNA mimics and antagomiRs, can alter the expression of specific genes involved in cancer development. miRNA mimics, such as miR-34, have been used to inhibit tumor growth, while antagomiRs, such as anti-miR-10b, have been used to inhibit metastasis. The development of epi-drugs that target specific epigenetic changes may lead to more effective monotherapy options in the future.
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Neoplasias da Mama , MicroRNAs , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Metilação de DNA , MicroRNAs/metabolismo , Código das Histonas , Antagomirs/metabolismo , Epigênese Genética , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Metiltransferases/metabolismo , DNA/metabolismoRESUMO
Oligonucleotide therapies offer precision treatments for a variety of neurological diseases, including epilepsy, but their deployment is hampered by the blood-brain barrier (BBB). Previous studies showed that intracerebroventricular injection of an antisense oligonucleotide (antagomir) targeting microRNA-134 (Ant-134) reduced evoked and spontaneous seizures in animal models of epilepsy. In this study, we used assays of serum protein and tracer extravasation to determine that BBB disruption occurring after status epilepticus in mice was sufficient to permit passage of systemically injected Ant-134 into the brain parenchyma. Intraperitoneal and intravenous injection of Ant-134 reached the hippocampus and blocked seizure-induced upregulation of miR-134. A single intraperitoneal injection of Ant-134 at 2 h after status epilepticus in mice resulted in potent suppression of spontaneous recurrent seizures, reaching a 99.5% reduction during recordings at 3 months. The duration of spontaneous seizures, when they occurred, was also reduced in Ant-134-treated mice. In vivo knockdown of LIM kinase-1 (Limk-1) increased seizure frequency in Ant-134-treated mice, implicating de-repression of Limk-1 in the antagomir mechanism. These studies indicate that systemic delivery of Ant-134 reaches the brain and produces long-lasting seizure-suppressive effects after systemic injection in mice when timed with BBB disruption and may be a clinically viable approach for this and other disease-modifying microRNA therapies.
Assuntos
Antagomirs/genética , Barreira Hematoencefálica/metabolismo , Epilepsia/genética , Epilepsia/terapia , Animais , Antagomirs/administração & dosagem , Barreira Hematoencefálica/patologia , Gerenciamento Clínico , Modelos Animais de Doenças , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Inativação Gênica , Técnicas de Transferência de Genes , Predisposição Genética para Doença , Terapia Genética , Camundongos , MicroRNAs/genética , Interferência de RNA , Resultado do TratamentoRESUMO
MicroRNAs (miRNAs) act as master regulators of gene expression in homeostasis and disease. Despite the rapidly growing body of evidence on the theranostic potential of restoring miRNA levels in pre-clinical models, the translation into clinics remains limited. Here, we review the current knowledge of miRNAs as T-cell targeting immunotherapeutic tools, and we offer an overview of the recent advances in miRNA delivery strategies, clinical trials and future perspectives in RNA interference technologies.
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MicroRNAs , MicroRNAs/genética , MicroRNAs/uso terapêutico , Linfócitos T , Interferência de RNA , Medicina de Precisão , ImunoterapiaRESUMO
The term epileptogenesis defines the usually durable process of converting normal brain into an epileptic one. The resistance of a significant proportion of patients with epilepsy to the available pharmacotherapy prompted the concept of a causative treatment option consisting in stopping or modifying the progress of epileptogenesis. Most antiepileptic drugs possess only a weak or no antiepileptogenic potential at all, but a few of them appear promising in this regard; these include, for example, eslicarbazepine (a sodium and T-type channel blocker), lamotrigine (a sodium channel blocker and glutamate antagonist) or levetiracetam (a ligand of synaptic vehicle protein SV2A). Among the approved non-antiepileptic drugs, antiepileptogenic potential seems to reside in losartan (a blocker of angiotensin II type 1 receptors), biperiden (an antiparkinsonian drug), nonsteroidal anti-inflammatory drugs, antioxidative drugs and minocycline (a second-generation tetracycline with anti-inflammatory and antioxidant properties). Among other possible antiepileptogenic compounds, antisense nucleotides have been considered, among these an antagomir targeting microRNA-134. The drugs and agents mentioned above have been evaluated in post-status epilepticus models of epileptogenesis, so their preventive efficacy must be verified. Limited clinical data indicate that biperiden in patients with brain injuries is well-tolerated and seems to reduce the incidence of post-traumatic epilepsy. Exceptionally, in this regard, our own original data presented here point to c-Fos as an early seizure duration, but not seizure intensity-related, marker of early epileptogenesis. Further research of reliable markers of early epileptogenesis is definitely needed to improve the process of designing adequate antiepileptogenic therapies.
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Anticonvulsivantes/farmacologia , Biomarcadores , Suscetibilidade a Doenças , Descoberta de Drogas , Epilepsia/etiologia , Epilepsia/metabolismo , Animais , Anticonvulsivantes/química , Antioxidantes/administração & dosagem , Terapia Combinada , Suplementos Nutricionais , Descoberta de Drogas/métodos , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Humanos , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas c-fos/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Mesial temporal lobe epilepsy (mTLE) is a chronic neurological disease characterized by recurrent seizures. The antiepileptic drugs currently available to treat mTLE are ineffective in one-third of patients and lack disease-modifying effects. miRNAs, a class of small noncoding RNAs which control gene expression at the post-transcriptional level, play a key role in the pathogenesis of mTLE and other epilepsies. Although manipulation of miRNAs at acute stages has been reported to reduce subsequent spontaneous seizures, it is uncertain whether targeting miRNAs at chronic stages of mTLE can also reduce seizures. Furthermore, the functional role and downstream targets of most epilepsy-associated miRNAs remain poorly understood. Here, we show that miR-135a is selectively upregulated within neurons in epileptic brain and report that targeting miR-135a in vivo using antagomirs after onset of spontaneous recurrent seizures can reduce seizure activity at the chronic stage of experimental mTLE in male mice. Further, by using an unbiased approach combining immunoprecipitation and RNA sequencing, we identify several novel neuronal targets of miR-135a, including Mef2a Mef2 proteins are key regulators of excitatory synapse density. Mef2a and miR-135a show reciprocal expression regulation in human (of both sexes) and experimental TLE, and miR-135a regulates dendritic spine number and type through Mef2. Together, our data show that miR-135a is target for reducing seizure activity in chronic epilepsy, and that deregulation of miR-135a in epilepsy may alter Mef2a expression and thereby affect synaptic function and plasticity.SIGNIFICANCE STATEMENT miRNAs are post-transcriptional regulators of gene expression with roles in the pathogenesis of epilepsy. However, the precise mechanism of action and therapeutic potential of most epilepsy-associated miRNAs remain poorly understood. Our study reveals dramatic upregulation of the key neuronal miRNA miR-135a in both experimental and human mesial temporal lobe epilepsy. Silencing miR-135a in experimental temporal lobe epilepsy reduces seizure activity at the spontaneous recurrent seizure stage. These data support the exciting possibility that miRNAs can be targeted to combat seizures after spontaneous seizure activity has been established. Further, by using unbiased approaches novel neuronal targets of miR-135a, including members of the Mef2 protein family, are identified that begin to explain how deregulation of miR-135a may contribute to epilepsy.
Assuntos
Antagomirs/uso terapêutico , Epilepsia do Lobo Temporal/tratamento farmacológico , Hipocampo/efeitos dos fármacos , MicroRNAs/antagonistas & inibidores , Convulsões/tratamento farmacológico , Animais , Antagomirs/farmacologia , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/metabolismo , Hipocampo/metabolismo , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Convulsões/genética , Convulsões/metabolismo , Resultado do TratamentoRESUMO
The analysis of epigenetic modifications in allergic diseases has recently attracted substantial interest because epigenetic modifications can mediate the effects of the environment on the development of or protection from allergic diseases. Furthermore, recent research has provided evidence for an altered epigenomic landscape in disease-relevant cell populations. Although still in the early phase, epigenetic modifications, particularly DNA methylation and microRNAs, might have potential for assisting in the stratification of patients for treatment and complement or replace in the future biochemical or clinical tests. The first epigenetic biomarkers correlating with the successful outcome of immunotherapy have been reported, and with personalized treatment options being rolled out, epigenetic modifications might well play a role in monitoring or even predicting the response to tailored therapy. However, further studies in larger cohorts with well-defined phenotypes in specific cell populations need to be performed before their implementation. Furthermore, the epigenome provides an interesting target for therapeutic intervention, with microRNA mimics, inhibitors, and antisense oligonucleotides being evaluated in clinical trials in patients with other diseases. Selection or engineering of populations of extracellular vesicles and epigenetic editing represent novel tools for modulation of the cellular phenotype and responses, although further technological improvements are required. Moreover, interactions between the host epigenome and the microbiome are increasingly recognized, and interventions of the microbiome could contribute to modulation of the epigenome with a potential effect on the overall goal of prevention of allergic diseases.
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Epigênese Genética , Hipersensibilidade/genética , Animais , Metilação de DNA , Epigenômica , Vesículas Extracelulares , Humanos , MicroRNAsRESUMO
MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene-expression posttranscriptionally. MiRNA research in allergy is expanding because miRNAs are crucial regulators of gene expression and promising candidates for biomarker development. MiRNA mimics and miRNA inhibitors currently in preclinical development have shown promise as novel therapeutic agents. Multiple technological platforms have been developed for miRNA isolation, miRNA quantitation, miRNA profiling, miRNA target detection, and modulating miRNA levels in vitro and in vivo. Here we will review the major technological platforms with consideration given for the advantages and disadvantages of each platform.
Assuntos
Hipersensibilidade/genética , MicroRNAs , Regulação da Expressão Gênica , Marcadores Genéticos , Humanos , Hipersensibilidade/tratamento farmacológico , Hipersensibilidade/metabolismo , Técnicas In Vitro , MicroRNAs/genética , MicroRNAs/isolamento & purificação , MicroRNAs/metabolismo , MicroRNAs/uso terapêuticoRESUMO
In T lymphocytes, expression of miR-148a is induced by T-bet and Twist1, and is specific for pro-inflammatory Th1 cells. In these cells, miR-148a inhibits the expression of the pro-apoptotic protein Bim and promotes their survival. Here we use sequence-specific cholesterol-modified oligonucleotides against miR-148a (antagomir-148a) for the selective elimination of pro-inflammatory Th1 cells in vivo. In the murine model of transfer colitis, antagomir-148a treatment reduced the number of pro-inflammatory Th1 cells in the colon of colitic mice by 50% and inhibited miR-148a expression by 71% in the remaining Th1 cells. Expression of Bim protein in colonic Th1 cells was increased. Antagomir-148a-mediated reduction of Th1 cells resulted in a significant amelioration of colitis. The effect of antagomir-148a was selective for chronic inflammation. Antigen-specific memory Th cells that were generated by an acute immune reaction to nitrophenylacetyl-coupled chicken gamma globulin (NP-CGG) were not affected by treatment with antagomir-148a, both during the effector and the memory phase. In addition, antibody titers to NP-CGG were not altered. Thus, antagomir-148a might qualify as an effective drug to selectively deplete pro-inflammatory Th1 cells of chronic inflammation without affecting the protective immunological memory.
Assuntos
Antagomirs/genética , Colite/imunologia , Colo/imunologia , Inflamação/imunologia , MicroRNAs/genética , Células Th1/fisiologia , Animais , Diferenciação Celular , Células Cultivadas , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Proteína 1 Relacionada a Twist/genética , Proteína 1 Relacionada a Twist/metabolismoRESUMO
PURPOSE: We investigated whether miRNAs in exosomes from EMT6 or 4THM tumor-bearing mice played a role in regulating inflammatory cytokine expression and/or metastasis in WT mice injected with EMT6 and/or 4THM tumor cells. METHODS: EMT6 tumors in BALB/c CD200R1KO mice resolve following surgical resection of localized tumor and immunization with irradiated EMT6 cells along with CpG as adjuvant. Wild-type (WT) animals treated in the same fashion develop pulmonary and liver metastases within 20 days of surgery. DLNs from CD200R1KO mice contain no tumor cells detectable at limiting dilution. In contrast, 4THM tumor cells injected into CD200R1KO show increased metastasis compared with WT mice. Transfer of serum exosomes from 4THM tumor-bearing mice to WT animals increased metastasis of EMT6 tumors, an effect attenuated by anti-IL-6 antibody. We compared miRNA expression in exosomes from the serum of 4THM/EMT6 WT or CD200R1KO tumor-bearing mice, and the effects of antagomirs to miRNAs on tumor growth. RESULTS: Complex changes in miRNA expression were observed in the isolated exosomes. Some miRNAs, including miR155, have been reported to potentiate inflammatory responses and augment inflammatory cytokine expression. Expression of miR155 increased in exosomes from 4THM relative to EMT6 tumor bearers, and antagomirs to miR155 attenuated tumor growth and metastasis, and improved survival, following infusion into WT mice. Antagomirs to the miR205 family were thought to affect metastasis by targeting epithelial-to-mesenchymal transition (EMT), increased growth and metastasis in both 4THM and EMT6 tumor-bearing mice, and decreased survival, with some modulation of inflammatory cytokine production. CONCLUSIONS: Multiple pathways are implicated in differential metastasis of EMT6/4THM, and targeting these may have clinical utility in human breast cancer.
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Neoplasias da Mama/genética , Neoplasias da Mama/patologia , MicroRNAs/genética , Receptores de Orexina/deficiência , Animais , Neoplasias da Mama/sangue , Linhagem Celular Tumoral , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Exossomos/metabolismo , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/sangue , Metástase Neoplásica , TranscriptomaRESUMO
Adenosine-to-inosine deamination can be re-addressed to user-defined mRNAs by applying phosphothioate/2'-methoxy-modified guideRNAs. Dense chemical modification of the guideRNA clearly improves performance of the covalent conjugates inside the living cell. Furthermore, careful positioning of a few modifications controls editing selectivity in vitro and was exploited for the challenging repair of the Factorâ 5 Leiden missense mutation.
Assuntos
RNA/metabolismo , Técnicas de Cultura de Células , DesaminaçãoRESUMO
BACKGROUND: Publications reveal different outcomes achieved by genetically knocking out a long non-coding microRNA-host-gene (lncMIRHG) versus the administration of pharma-cologic antagomirs specifically targeting the guide strand of such intragenic microRNA. This suggests that lncMIRHGs may perform diverse functions unrelated to their role as intragenic miRNA precursors. OBJECTIVE: This review synthesizes in silico, in vitro, and in vivo findings from our lab and others to compare the effects of knocking out the long non-coding RNA MIR22HG, which hosts miR-22, versus administering pharmacological antagomirs targeting miR-22-3p. METHODS: In silico analyses at the gene, pathway, and network levels reveal both distinct and overlapping targets of hsa-miR-22-3p and its host gene, MIR22HG. While pharmacological an-tagomirs targeting miR-22-3p consistently improve various metabolic parameters in cell culture and animal models across multiple studies, genetic knockout of MIR22HG yields inconsistent results among different research groups. RESULTS: Additionally, MIR22HG functions as a circulating endogenous RNA (ceRNA) or "sponge" that simultaneously modulates multiple miRNA-mRNA interactions by competing for binding to several miRNAs. CONCLUSIONS: From a therapeutic viewpoint, genetic inactivation of a lncMIRHG and pharmaco-logic antagonism of the guide strand of its related intragenic miRNA produce different results. This should be expected as lncMIRHGs play dual roles, both as lncRNA and as a source for primary miRNA transcripts.
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OBJECTIVES: The study aimed to identify a quantitative signature of circulating small non-coding RNAs (sncRNAs) as a biomarker for pulmonary tuberculosis disease (active-TB/ATB) and explore their regulatory roles in host-pathogen interactions and disease progression. METHODS: We conducted a cross-sectional study recruiting subjects diagnosed with active-TB (drug-sensitive and drug-resistant) and healthy controls. Sera samples were collected and utilized for preparing small RNA libraries. Quantitative patterns of circulating sncRNAs (miRNAs, piRNAs and tRFs) were identified via high-throughput sequencing and DeSeq2 analysis and validated in independent active-TB cohorts. Functional knockdown for two selected miRNAs were also performed. RESULTS: A diagnostic signature of four sncRNAs for both drug-sensitive and drug-resistant active-TB cases was validated, exhibiting an AUC of 0.96 (95% CI: 0.937-0.996, p < 0.001) with 86.7% sensitivity (95% CI: 0.775-0.932) and 91.7% specificity (95% CI: 0.730-0.990) in ROC analysis. Functional knockdown demonstrated regulatory roles of hsa-miR-223-5p and hsa-miR-10b-5p in Mycobacterium tuberculosis (Mtb) growth and pro-inflammatory cytokine expression (IL-6 and IL-8). CONCLUSION: The study identified a diagnostic tool utilizing a signature of four sncRNAs with high specificity and sensitivity, enhancing our understanding of sncRNAs as ATB diagnostic biomarker. Additionally, hsa-miR-223-5p and hsa-miR-10b-5p demonstrated potential roles in Mtb pathogenesis and host-response to infection.
Assuntos
Biomarcadores , Humanos , Biomarcadores/sangue , Feminino , Masculino , Adulto , Tuberculose Pulmonar/diagnóstico , Tuberculose Pulmonar/genética , Tuberculose Pulmonar/sangue , Tuberculose Pulmonar/microbiologia , Interações Hospedeiro-Patógeno/genética , Pequeno RNA não Traduzido/genética , Pessoa de Meia-Idade , MicroRNAs/genética , MicroRNAs/sangue , Tuberculose/diagnóstico , Tuberculose/genética , Tuberculose/microbiologia , Tuberculose/sangue , Estudos Transversais , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Estudos de Casos e Controles , Curva ROC , Mycobacterium tuberculosis/genéticaRESUMO
First oligonucleotide analogues that inhibit miRNA function are currently investigated in clinical trials. In addition, several alternative methods are under development that may allow for controlling miRNA function by small molecules-mediated inhibiting of its biogenesis. In this perspectives article, we provide a short overview on recent developments in this field.
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MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Oligonucleotídeos/farmacologia , HumanosRESUMO
It is now well established that lifestyle, particularly eating habits, modulates the synthesis and action of microRNAs (miRNAs). In particular, several nutritional schemes have proven effective in improving body composition, but molecular mechanisms still need to be fully understood. Within the complex physiological network of food intake regulation, it is essential to understand the changes in endocrine activity after the reduction of adipose tissue during a weight loss program. This could be the key to identifying the optimal endocrine profile in high responders, the assessment of musculoskeletal status, and long-term management. In this review, we summarize the state of the art regarding miRNAs as a function of weight loss and as a mechanistic regulator of the effectiveness of the nutritional program.
Assuntos
MicroRNAs , Humanos , MicroRNAs/genética , Obesidade/genética , Dieta Redutora , Redução de Peso/genética , Tecido AdiposoRESUMO
Non-coding RNAs comprise the majority of RNAs that have been transcribed from the human genome, and these non-coding RNAs have essential regulatory roles in the cellular processes. They have been discovered to influence the expression of the genes, including tumorsuppressive and oncogenes, that establish the non-coding RNAs as novel targets for anti-cancer drug development. Among non-coding RNAs, microRNAs have been extensively studied in terms of cancer biology, and some microRNA-based therapeutics have been reached in clinical studies. Even though most of the research regarding targeting non-coding RNAs for anti-cancer drug development focused on microRNAs, long non-coding RNAs have also started to gain importance as potential therapeutic targets for cancer therapy. In this chapter, the strategies and importance of targeting microRNAs and long non-coding RNAs will be described, along with the clinical studies that involve microRNA-based cancer therapeutics and preclinical studies that involve long noncoding RNA-based therapeutics. Finally, the delivery strategies that have great importance in the effective delivery of the non-coding RNA-based cancer therapeutics, hence the therapy's effectiveness, will be described.
Assuntos
Antineoplásicos , MicroRNAs , Neoplasias , RNA Longo não Codificante , Humanos , MicroRNAs/genética , MicroRNAs/uso terapêutico , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Regulação Neoplásica da Expressão Gênica , Neoplasias/tratamento farmacológico , Neoplasias/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêuticoRESUMO
Skin inflammation is a common underlying feature of atopic dermatitis, allergic contact dermatitis and chronic spontaneous urticaria. The pathogenetic mechanisms have not been fully elucidated. The purpose of this study was to examine whether miRNA, by regulating inflammatory mechanisms through the modulation of innate and adaptive immune responses, could play a major role in the pathogenesis of these skin conditions. We conducted a narrative review using the Pubmed and Embase scientific databases and search engines to find the most relevant miRNAs related to the pathophysiology, severity and prognosis of skin conditions. The studies show that miRNAs are involved in the pathogenesis and regulation of atopic dermatitis and can reveal an atopic predisposition or indicate disease severity. In chronic spontaneous urticaria, different miRNAs which are over-expressed during urticaria exacerbations not only play a role in the possible response to therapy or remission, but also serve as a marker of chronic autoimmune urticaria and indicate associations with other autoimmune diseases. In allergic contact dermatitis, miRNAs are upregulated in inflammatory lesions and expressed during the sensitization phase of allergic response. Several miRNAs have been identified as potential biomarkers of these chronic skin conditions, but they are also possible therapeutic targets.
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In diabetes, possibly the most significant site of microvascular damage is the kidney. Due to diabetes and/or other co-morbidities, such as hypertension and age-related nephron loss, a significant number of people with diabetes suffer from kidney diseases. Improved diabetic care can reduce the prevalence of diabetic nephropathy (DN); however, innovative treatment approaches are still required. MicroRNA-21 (miR-21) is one of the most studied multipotent microRNAs (miRNAs), and it has been linked to renal fibrosis and exhibits significantly altered expression in DN. Targeting miR-21 offers an advantage in DN. Currently, miR-21 is being pharmacologically silenced through various methods, all of which are in early development. In this review, we summarize the role of miR-21 in the molecular pathogenesis of DN and several therapeutic strategies to use miR-21 as a therapeutic target in DN. The existing experimental interventions offer a way to rectify the lower miRNA levels as well as to reduce the higher levels. Synthetic miRNAs also referred to as miR-mimics, can compensate for abnormally low miRNA levels. Furthermore, strategies like oligonucleotides can be used to alter the miRNA levels. It is reasonable to target miR-21 for improved results because it directly contributes to the pathological processes of kidney diseases, including DN.