3,946 research outputs found

    MicroRNA-mediated regulation of Nrf2 signaling pathway: Implications in disease therapy and protection against oxidative stress

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    MicroRNAs (miRs) are small non-coding pieces of RNA that are involved in a variety of physiologic processes such as apoptosis, cell proliferation, cell differentiation, cell cycle and cell survival. These multifunctional nucleotides are also capable of preventing oxidative damages by modulating antioxidant defense systems in a variety of milieu, such as in diabetes. Although the exact molecular mechanisms by which miRs modulate the antioxidant defense elements are unclear, some evidence suggests that they may exert these effects via nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway. This intracellular mechanism is crucial in the maintenance of the physiologic redox balance by regulating the expression and activity of various cellular antioxidative defense elements and thereby plays a pivotal role in the development of oxidative stress. Any impairment in the Nrf2 signaling pathway may result in oxidative damage-dependent complications such as various diabetic complications, neurological disorders and cancer. In the current review, we discuss the modulatory effects of miRs on the Nrf2 signaling pathway, which can potentially be novel therapeutic targets

    The Role of Dysregulated miRNAs in the Pathogenesis, Diagnosis and Treatment of Age-Related Macular Degeneration

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    Age-related macular degeneration (AMD) is an eye disease causing damage to the macular region of the retina where most of the photoreceptors responsible for central visual acuity are located. MicroRNAs (miRNAs) are small single-stranded non-coding RNA molecules that negatively regulate genes by silent post-transcriptional gene expressions. Previous studies have shown that changes in specific miRNAs are involved in the pathogenesis of eye diseases, including AMD. Altered expressions of miRNAs are related to disturbances of regulating oxidative stress, inflammation, angiogenesis, apoptosis and phagocytosis, which are known factors in the pathogenesis of AMD. Moreover, dysregulation of miRNA is involved in drusen formation. Thus, miRNAs may be used as potential molecular biomarkers for the disease and, furthermore, tailoring therapeutics to particular disturbances in miRNAs may, in the future, offer hope to prevent irreversible vision loss. In this review, we clarify the current state of knowledge about the influence of miRNA on the pathogenesis, diagnosis and treatment of AMD. Our study material consisted of publications, which were found in PubMed, Google Scholar and Embase databases using "Age-related macular degeneration", "miRNA", "AMD biomarkers", "miRNA therapeutics" and "AMD pathogenesis" as keywords. Paper search was limited to articles published from 2011 to date. In the section "Retinal, circulating and vitreous body miRNAs found in human studies", we limited the search to studies with patients published in 2016-2021

    Regulatory Role of Non-Coding RNAs on Immune Responses During Sepsis

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    Sepsis is resulted from a systemic inflammatory response to bacterial, viral, or fungal agents. The induced inflammatory response by these microorganisms can lead to multiple organ system failure with devastating consequences. Recent studies have shown altered expressions of several non-coding RNAs such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs) during sepsis. These transcripts have also been found to participate in the pathogenesis of multiple organ system failure through different mechanisms. NEAT1, MALAT1, THRIL, XIST, MIAT and TUG1 are among lncRNAs that participate in the pathoetiology of sepsis-related complications. miR-21, miR-155, miR-15a-5p, miR-494-3p, miR-218, miR-122, miR-208a-5p, miR-328 and miR-218 are examples of miRNAs participating in these complications. Finally, tens of circRNAs such as circC3P1, hsa_circRNA_104484, hsa_circRNA_104670 and circVMA21 and circ-PRKCI have been found to affect pathogenesis of sepsis. In the current review, we describe the role of these three classes of noncoding RNAs in the pathoetiology of sepsis-related complications

    Non-Coding RNAs in Cell-to-Cell Communication: Exploiting Physiological Mechanisms as Therapeutic Targets in Cardiovascular Pathologies

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    Cardiovascular disease, the leading cause of death worldwide, has been characterized at the molecular level by alterations in gene expression that contribute to the etiology of the disease. Such alterations have been shown to play a critical role in the development of atherosclerosis, cardiac remodeling, and age-related heart failure. Although much is now known about the cellular and molecular mechanisms in this context, the role of epigenetics in the onset of cardiovascular disease remains unclear. Epigenetics, a complex network of mechanisms that regulate gene expression independently of changes to the DNA sequence, has been highly implicated in the loss of homeostasis and the aberrant activation of a myriad of cellular pathways. More specifically, non-coding RNAs have been gaining much attention as epigenetic regulators of various pathologies. In this review, we will provide an overview of the ncRNAs involved in cell-to-cell communication in cardiovascular disease, namely atherosclerosis, cardiac remodeling, and cardiac ageing, and the potential use of epigenetic drugs as novel therapeutic targets

    An update on the functional roles of long non‑coding RNAs in ischemic injury (Review)

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    Ischemic injuries result from ischemia and hypoxia in cells. Tissues and organs receive an insufficient supply of nutrients and accumulate metabolic waste, which leads to the development of inflammation, fibrosis and a series of other issues. Ischemic injuries in the brain, heart, kidneys, lungs and other organs can cause severe adverse effects. Acute renal ischemia induces acute renal failure, heart ischemia induces myocardial infarction and cerebral ischemia induces cerebrovascular accidents, leading to loss of movement, consciousness and possibly, life-threatening disabilities. Existing evidence suggests that long non-coding RNAs (lncRNAs) are regulatory sequences involved in transcription, post-transcription, epigenetic regulation and multiple physiological processes. lncRNAs have been shown to be differentially expressed following ischemic injury, with the severity of the ischemic injury being affected by the upregulation or downregulation of certain types of lncRNA. The present review article provides an extensive summary of the functional roles of lncRNAs in ischemic injury, with a focus on the brain, heart, kidneys and lungs. The present review mainly summarizes the functional roles of lncRNA MALAT1, lncRNA MEG3, lncRNA H19, lncRNA TUG1, lncRNA NEAT1, lncRNA AK139328 and lncRNA CAREL, among which lncRNA MALAT1, in particular, plays a crucial role in ischemic injury and is currently a hot research topic

    The role of microRNAs in newborn brain development and hypoxic ischaemic encephalopathy.

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    Neonates can develop hypoxic-ischaemic encephalopathy (HIE) due to lack of blood supply or oxygen, resulting in a major cause of death and disability among term newborns. However, current definitive treatment of therapeutic hypothermia, will only benefit one out of nine babies. Furthermore, the mechanisms of HIE and therapeutic hypothermia are not fully understood. Recently, microRNAs (miRNAs) have become of interest to many researchers due to their important role in post-transcriptional control and deep evolutionary history. Despite this, role of miRNAs in newborns with HIE remains largely unknown due to limited research in this field. Therefore, this review aims to understand the role of miRNAs in normal brain development and HIE pathophysiology with reliance on extrapolated data from other diseases, ages and species due to current limited data. This will provide us with an overview of how miRNAs in normal brain development changes after HIE. Furthermore, it will indicate how miRNAs are affected specifically or globally by the various pathophysiological events. In addition, we discuss about how drugs and commercially available agents can specifically target certain miRNAs as a mechanism of action and potential safety issue with off-target effects. Improving our understanding of the role of miRNAs on the cellular response after HIE would enhance the success of effective diagnosis, prognosis, and treatment of newborns with HIE

    Role of hypoxia in cellular senescence

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    This work was supported by the National Natural Science Foundation of China (Grant no. 31972741) ; MH CZ-DRO (UHHK, 00179906) ; Grant Agency of the Czech Republic (20-22037S) ; Research Program of University of Granada; and Scientific Grant Agency (VEGA Project 1/0482/20).Senescent cells persist and continuously secrete proinflammatory and tissue-remodeling molecules that poison surrounding cells, leading to various age-related diseases, including diabetes, atherosclerosis, and Alzheimer's disease. The underlying mechanism of cellular senescence has not yet been fully explored. Emerging evidence indicates that hypoxia is involved in the regulation of cellular senescence. Hypoxia-inducible factor (HIF)-1 alpha accumulates under hypoxic conditions and regulates cellular senescence by modulating the levels of the senescence markers p16, p53, lamin B1, and cyclin D1. Hypoxia is a critical condition for maintaining tumor immune evasion, which is promoted by driving the expression of genetic factors (such as p53 and CD47) while triggering immunosenescence. Under hypoxic conditions, autophagy is activated by targeting BCL-2/adenovirus E1B 19kDa interacting protein 3, which subsequently induces p21(WAF1/CIP1) as well as p16(Ink4a) and increases beta-galactosidase (beta-gal) activity, thereby inducing cellular senescence. Deletion of the p21 gene increases the activity of the hypoxia response regulator poly (ADP-ribose) polymerase-1 (PARP-1) and the level of nonhomologous end joining (NHEJ) proteins, repairs DNA double-strand breaks, and alleviates cellular senescence. Moreover, cellular senescence is associated with intestinal dysbiosis and an accumulation of D-galactose derived from the gut microbiota. Chronic hypoxia leads to a striking reduction in the amount of Lactobacillus and D-galactose-degrading enzymes in the gut, producing excess reactive oxygen species (ROS) and inducing senescence in bone marrow mesenchymal stem cells. Exosomal microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) play important roles in cellular senescence. miR-424-5p levels are decreased under hypoxia, whereas lncRNA-MALAT1 levels are increased, both of which induce cellular senescence. The present review focuses on recent advances in understanding the role of hypoxia in cellular senescence. The effects of HIFs, immune evasion, PARP-1, gut microbiota, and exosomal mRNA in hypoxia-mediated cell senescence are specifically discussed. This review increases our understanding of the mechanism of hypoxia-mediated cellular senescence and provides new clues for anti-aging processes and the treatment of aging-related diseases.National Natural Science Foundation of China (NSFC) 31972741MH CZ-DRO (UHHK) 00179906Grant Agency of the Czech Republic Norwegian Agency for Development Cooperation - NORAD 20-22037SResearch Program of University of GranadaVedecka grantova agentura MSVVaS SR a SAV (VEGA) 1/0482/2

    MicroRNAs and obesity-induced endothelial dysfunction: key paradigms in molecular therapy

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    The endothelium plays a pivotal role in maintaining vascular health. Obesity is a global epidemic that has seen dramatic increases in both adult and pediatric populations. Obesity perturbs the integrity of normal endothelium, leading to endothelial dysfunction which predisposes the patient to cardiovascular diseases. MicroRNAs (miRNAs) are short, single-stranded, non-coding RNA molecules that play important roles in a variety of cellular processes such as differentiation, proliferation, apoptosis, and stress response; their alteration contributes to the development of many pathologies including obesity. Mediators of obesity-induced endothelial dysfunction include altered endothelial nitric oxide synthase (eNOS), Sirtuin 1 (SIRT1), oxidative stress, autophagy machinery and endoplasmic reticulum (ER) stress. All of these factors have been shown to be either directly or indirectly caused by gene regulatory mechanisms of miRNAs. In this review, we aim to provide a comprehensive description of the therapeutic potential of miRNAs to treat obesity-induced endothelial dysfunction. This may lead to the identification of new targets for interventions that may prevent or delay the development of obesity-related cardiovascular disease.ope

    MicroRNA Alterations Induced in Human Skin by Diesel Fumes, Ozone, and UV Radiation

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    Epigenetic alterations are a driving force of the carcinogenesis process. MicroRNAs play a role in silencing mutated oncogenes, thus defending the cell against the adverse consequences of genotoxic damages induced by environmental pollutants. These processes have been well investigated in lungs; however, although skin is directly exposed to a great variety of environmental pollutants, more research is needed to better understand the effect on cutaneous tissue. Therefore, we investigated microRNA alteration in human skin biopsies exposed to diesel fumes, ozone, and UV light for over 24 h of exposure. UV and ozone-induced microRNA alteration right after exposure, while the peak of their deregulations induced by diesel fumes was reached only at the end of the 24 h. Diesel fumes mainly altered microRNAs involved in the carcinogenesis process, ozone in apoptosis, and UV in DNA repair. Accordingly, each tested pollutant induced a specific pattern of microRNA alteration in skin related to the intrinsic mechanisms activated by the specific pollutant. These alterations, over a short time basis, reflect adaptive events aimed at defending the tissue against damages. Conversely, whenever environmental exposure lasts for a long time, the irreversible alteration of the microRNA machinery results in epigenetic damage contributing to the pathogenesis of inflammation, dysplasia, and cancer induced by environmental pollutants
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