International Journal of Molecular Sciences

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17 pages, 4519 KiB

Open AccessArticle

Interrogating the Role of miR-125b and Its 3′isomiRs in Protection against Hypoxia

by Lee Lee Wong, Azizah Binti Fadzil, Qiying Chen, Miriam T. Rademaker, Christopher J. Charles, Arthur Mark Richards and Peipei Wang

Int. J. Mol. Sci. 2023, 24(21), 16015; https://doi.org/10.3390/ijms242116015 - 6 Nov 2023

Cited by 1 | Viewed by 1019

Abstract

MiR-125b has therapeutic potential in the amelioration of myocardial ischemic injury. MicroRNA isomiRs, with either 5′ or 3′ addition or deletion of nucleotide(s), have been reported from next-generation sequencing data (NGS). However, due to technical challenges, validation and functional studies of isomiRs are [...] Read more.

MiR-125b has therapeutic potential in the amelioration of myocardial ischemic injury. MicroRNA isomiRs, with either 5′ or 3′ addition or deletion of nucleotide(s), have been reported from next-generation sequencing data (NGS). However, due to technical challenges, validation and functional studies of isomiRs are few. In this study, we discovered using NGS, four 3′isomiRs of miR-125b, i.e., addition of A (adenosine), along with deletions of A, AG (guanosine) and AGU (uridine) from rat and sheep heart. These findings were validated using RT-qPCR. Comprehensive functional studies were carried out in the H9C2 hypoxia model. After miR-125b, isomiRs of Plus A, Trim A, AG and AGU mimic transfection, the H9C2 cells were subjected to hypoxic challenge. As assessed using cell viability, apoptosis, CCK-8 and LDH release, miR-125b and isomiRs were all protective against hypoxia. However, Plus A and Trim A were more effective than miR-125b, whilst Trim AG and Trim AGU had far weaker effects than miR-125b. Interestingly, both the gene regulation profile and apoptotic gene validation indicated a major overlap among miR-125b, Plus A and Trim A, whilst Trims AG and AGU revealed a different profile compared to miR-125b. Conclusions: miR-125b and its 3′ isomiRs are expressed stably in the heart. miR-125b and isomiRs with addition or deletion of A might function concurrently and concordantly under specific physiological and pathophysiological conditions. In-depth understanding of isomiRs’ metabolism and function will contribute to better miRNA therapeutic drug design. Full article

(This article belongs to the Special Issue Different Functions and Roles of microRNAs in Human Disease—Development, Progress and Challenges)

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Review

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28 pages, 760 KiB

Open AccessReview

Hepatitis B Virus and microRNAs: A Bioinformatics Approach

by Verdiana Zulian, Giulia Fiscon, Paola Paci and Anna Rosa Garbuglia

Int. J. Mol. Sci. 2023, 24(24), 17224; https://doi.org/10.3390/ijms242417224 - 7 Dec 2023

Viewed by 1426

Abstract

In recent decades, microRNAs (miRNAs) have emerged as key regulators of gene expression, and the identification of viral miRNAs (v-miRNAs) within some viruses, including hepatitis B virus (HBV), has attracted significant attention. HBV infections often progress to chronic states (CHB) and may induce [...] Read more.

In recent decades, microRNAs (miRNAs) have emerged as key regulators of gene expression, and the identification of viral miRNAs (v-miRNAs) within some viruses, including hepatitis B virus (HBV), has attracted significant attention. HBV infections often progress to chronic states (CHB) and may induce fibrosis/cirrhosis and hepatocellular carcinoma (HCC). The presence of HBV can dysregulate host miRNA expression, influencing several biological pathways, such as apoptosis, innate and immune response, viral replication, and pathogenesis. Consequently, miRNAs are considered a promising biomarker for diagnostic, prognostic, and treatment response. The dynamics of miRNAs during HBV infection are multifaceted, influenced by host variability and miRNA interactions. Given the ability of miRNAs to target multiple messenger RNA (mRNA), understanding the viral–host (human) interplay is complex but essential to develop novel clinical applications. Therefore, bioinformatics can help to analyze, identify, and interpret a vast amount of miRNA data. This review explores the bioinformatics tools available for viral and host miRNA research. Moreover, we introduce a brief overview focusing on the role of miRNAs during HBV infection. In this way, this review aims to help the selection of the most appropriate bioinformatics tools based on requirements and research goals. Full article

(This article belongs to the Special Issue Different Functions and Roles of microRNAs in Human Disease—Development, Progress and Challenges)

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23 pages, 3415 KiB

Open AccessReview

MicroRNA Dysregulation in Early Breast Cancer Diagnosis: A Systematic Review and Meta-Analysis

by Alejandro Garrido-Palacios, Ana María Rojas Carvajal, Ana María Núñez-Negrillo, Jonathan Cortés-Martín, Juan Carlos Sánchez-García and María José Aguilar-Cordero

Int. J. Mol. Sci. 2023, 24(9), 8270; https://doi.org/10.3390/ijms24098270 - 5 May 2023

Cited by 6 | Viewed by 2207

Abstract

Breast cancer continues to be the leading cause of death in women worldwide. Mammography, which is the current gold standard technique used to diagnose it, presents strong limitations in early ages where breast cancer is much more aggressive and fatal. MiRNAs present in [...] Read more.

Breast cancer continues to be the leading cause of death in women worldwide. Mammography, which is the current gold standard technique used to diagnose it, presents strong limitations in early ages where breast cancer is much more aggressive and fatal. MiRNAs present in numerous body fluids might represent a new line of research in breast cancer biomarkers, especially oncomiRNAs, known to play an important role in the suppression and development of neoplasms. The aim of this systematic review and meta-analysis was to evaluate dysregulated miRNA biomarkers and their diagnostic accuracy in breast cancer. Two independent researchers reviewed the included studies according to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. A protocol for this review was registered in PROSPERO with the registration number “CRD42021256338”. Observational case-control-based studies analyzing concentrations of microRNAs which have been published within the last 10 years were selected, and the concentrations of miRNAs in women with breast cancer and healthy controls were analyzed. Random-effects meta-analyses of miR-155 were performed on the studies which provided enough data to calculate diagnostic odds ratios. We determined that 34 microRNAs were substantially dysregulated and could be considered biomarkers of breast cancer. Individually, miR-155 provided better diagnostic results than mammography on average. However, when several miRNAs are used to screen, forming a panel, sensitivity and specificity rates improve, and they can be associated with classic biomarkers such us CA-125 or CEA. Based on the results of our meta-analysis, miR-155 might be a promising diagnostic biomarker for this patient population. Full article

(This article belongs to the Special Issue Different Functions and Roles of microRNAs in Human Disease—Development, Progress and Challenges)

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27 pages, 1663 KiB

Open AccessReview

Harnessing Epigenetics for Breast Cancer Therapy: The Role of DNA Methylation, Histone Modifications, and MicroRNA

by Joanna Szczepanek, Monika Skorupa, Joanna Jarkiewicz-Tretyn, Cezary Cybulski and Andrzej Tretyn

Int. J. Mol. Sci. 2023, 24(8), 7235; https://doi.org/10.3390/ijms24087235 - 13 Apr 2023

Cited by 10 | Viewed by 3121

Abstract

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 [...] Read more.

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. Full article

(This article belongs to the Special Issue Different Functions and Roles of microRNAs in Human Disease—Development, Progress and Challenges)

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24 pages, 1609 KiB

Open AccessReview

MicroRNAs and MAPKs: Evidence of These Molecular Interactions in Alzheimer’s Disease

by Ivana Raffaele, Serena Silvestro and Emanuela Mazzon

Int. J. Mol. Sci. 2023, 24(5), 4736; https://doi.org/10.3390/ijms24054736 - 1 Mar 2023

Cited by 4 | Viewed by 1937

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder known to be the leading cause of dementia worldwide. Many microRNAs (miRNAs) were found deregulated in the brain or blood of AD patients, suggesting a possible key role in different stages of neurodegeneration. In particular, mitogen-activated [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disorder known to be the leading cause of dementia worldwide. Many microRNAs (miRNAs) were found deregulated in the brain or blood of AD patients, suggesting a possible key role in different stages of neurodegeneration. In particular, mitogen-activated protein kinases (MAPK) signaling can be impaired by miRNA dysregulation during AD. Indeed, the aberrant MAPK pathway may facilitate the development of amyloid-beta (Aβ) and Tau pathology, oxidative stress, neuroinflammation, and brain cell death. The aim of this review was to describe the molecular interactions between miRNAs and MAPKs during AD pathogenesis by selecting evidence from experimental AD models. Publications ranging from 2010 to 2023 were considered, based on PubMed and Web of Science databases. According to obtained data, several miRNA deregulations may regulate MAPK signaling in different stages of AD and conversely. Moreover, overexpressing or silencing miRNAs involved in MAPK regulation was seen to improve cognitive deficits in AD animal models. In particular, miR-132 is of particular interest due to its neuroprotective functions by inhibiting Aβ and Tau depositions, as well as oxidative stress, through ERK/MAPK1 signaling modulation. However, further investigations are required to confirm and implement these promising results. Full article

(This article belongs to the Special Issue Different Functions and Roles of microRNAs in Human Disease—Development, Progress and Challenges)

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18 pages, 928 KiB

Open AccessReview

Oxidative Stress and Inflammation in Osteoporosis: Molecular Mechanisms Involved and the Relationship with microRNAs

by Teresa Iantomasi, Cecilia Romagnoli, Gaia Palmini, Simone Donati, Irene Falsetti, Francesca Miglietta, Cinzia Aurilia, Francesca Marini, Francesca Giusti and Maria Luisa Brandi

Int. J. Mol. Sci. 2023, 24(4), 3772; https://doi.org/10.3390/ijms24043772 - 14 Feb 2023

Cited by 34 | Viewed by 3671

Abstract

Osteoporosis is characterized by the alteration of bone homeostasis due to an imbalance between osteoclastic bone resorption and osteoblastic bone formation. Estrogen deficiency causes bone loss and postmenopausal osteoporosis, the pathogenesis of which also involves oxidative stress, inflammatory processes, and the dysregulation of [...] Read more.

Osteoporosis is characterized by the alteration of bone homeostasis due to an imbalance between osteoclastic bone resorption and osteoblastic bone formation. Estrogen deficiency causes bone loss and postmenopausal osteoporosis, the pathogenesis of which also involves oxidative stress, inflammatory processes, and the dysregulation of the expression of microRNAs (miRNAs) that control gene expression at post-transcriptional levels. Oxidative stress, due to an increase in reactive oxygen species (ROS), proinflammatory mediators and altered levels of miRNAs enhance osteoclastogenesis and reduce osteoblastogenesis through mechanisms involving the activation of MAPK and transcription factors. The present review summarizes the principal molecular mechanisms involved in the role of ROS and proinflammatory cytokines on osteoporosis. Moreover, it highlights the interplay among altered miRNA levels, oxidative stress, and an inflammatory state. In fact, ROS, by activating the transcriptional factors, can affect miRNA expression, and miRNAs can regulate ROS production and inflammatory processes. Therefore, the present review should help in identifying targets for the development of new therapeutic approaches to osteoporotic treatment and improve the quality of life of patients. Full article

(This article belongs to the Special Issue Different Functions and Roles of microRNAs in Human Disease—Development, Progress and Challenges)

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19 pages, 1538 KiB

Open AccessReview

The Role of MicroRNAs in Dilated Cardiomyopathy: New Insights for an Old Entity

by Elena Alonso-Villa, Fernando Bonet, Francisco Hernandez-Torres, Óscar Campuzano, Georgia Sarquella-Brugada, Maribel Quezada-Feijoo, Mónica Ramos, Alipio Mangas and Rocío Toro

Int. J. Mol. Sci. 2022, 23(21), 13573; https://doi.org/10.3390/ijms232113573 - 5 Nov 2022

Cited by 7 | Viewed by 2281

Abstract

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and systolic dysfunction. In most cases, DCM is progressive, leading to heart failure (HF) and death. This cardiomyopathy has been considered a common and final phenotype of several entities. [...] Read more.

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and systolic dysfunction. In most cases, DCM is progressive, leading to heart failure (HF) and death. This cardiomyopathy has been considered a common and final phenotype of several entities. DCM occurs when cellular pathways fail to maintain the pumping function. The etiology of this disease encompasses several factors, such as ischemia, infection, autoimmunity, drugs or genetic susceptibility. Although the prognosis has improved in the last few years due to red flag clinical follow-up, early familial diagnosis and ongoing optimization of treatment, due to its heterogeneity, there are no targeted therapies available for DCM based on each etiology. Therefore, a better understanding of the mechanisms underlying the pathophysiology of DCM will provide novel therapeutic strategies against this cardiac disease and their different triggers. MicroRNAs (miRNAs) are a group of small noncoding RNAs that play key roles in post-transcriptional gene silencing by targeting mRNAs for translational repression or, to a lesser extent, degradation. A growing number of studies have demonstrated critical functions of miRNAs in cardiovascular diseases (CVDs), including DCM, by regulating mechanisms that contribute to the progression of the disease. Herein, we summarize the role of miRNAs in inflammation, endoplasmic reticulum (ER) stress, oxidative stress, mitochondrial dysfunction, autophagy, cardiomyocyte apoptosis and fibrosis, exclusively in the context of DCM. Full article

(This article belongs to the Special Issue Different Functions and Roles of microRNAs in Human Disease—Development, Progress and Challenges)

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8 pages, 224 KiB

Open AccessReview

The Importance of MicroRNA Expression in Pseudoexfoliation Syndrome

by Martyna Tomczyk-Socha, Wojciech Tomczak and Anna Turno-Kręcicka

Int. J. Mol. Sci. 2022, 23(21), 13234; https://doi.org/10.3390/ijms232113234 - 31 Oct 2022

Cited by 4 | Viewed by 1147

Abstract

Pseudoexfoliation syndrome (PEX) is an important systemic disorder of the extracellular matrix, in which granular amyloid-like protein fibers accumulate in the anterior segment of the eyeball as well as in other organs. PEX is currently considered to be a multifactorial systemic disorder with [...] Read more.

Pseudoexfoliation syndrome (PEX) is an important systemic disorder of the extracellular matrix, in which granular amyloid-like protein fibers accumulate in the anterior segment of the eyeball as well as in other organs. PEX is currently considered to be a multifactorial systemic disorder with genetic and environmental risk factors. The aim of this manuscript was to analyze miR expression in PEX. In recent years, an attempt has been made to investigate and describe the level of expression of selected miRs in PEX. Four polymorphisms of genes isolated from the blood that may be related to PEX were identified and miR-122-5p was found to be upregulated in patient blood. Furthermore, 18 miRs were identified with a statistically different expression in the aqueous humor. A significantly elevated expression of miR-125b was found in the anterior lens capsule, and four miRs were described, which may have a significant impact on the development of PEX. Regulatory miR molecules are gaining more and more importance in research aimed at identifying and isolating molecular markers related to the pathogenesis and prognosis of PEX, but further studies are needed. Full article

(This article belongs to the Special Issue Different Functions and Roles of microRNAs in Human Disease—Development, Progress and Challenges)

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