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Non-Coding RNA, Volume 9, Issue 2 (April 2023) – 13 articles

Cover Story (view full-size image): MicroRNAs (miRNAs) are small non-coding RNAs regulating gene expression at the post-transcriptional level. MiRNAs have been found to have vital roles in various biological and pathological processes. In recent years, there has been an increase in the number of bioinformatic tools to assist in the massive demand in the field of miRNA research. Currently, such tools exist to aid researchers interested in various areas ranging from sequence annotation and validated miRNA targets to known associations with disease. Online web-based tools provide benefits to groups less experienced with programming and are regarded as more user friendly allowing accessibility to a wider range of audiences. In this brief review, such tools are categorised according to their primary purpose and will be introduced to highlight the diverse roles that miRNAs possess. View this paper
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11 pages, 2147 KiB  
Communication
The Cystic Fibrosis Transmembrane Conductance Regulator Gene (CFTR) Is under Post-Transcriptional Control of microRNAs: Analysis of the Effects of agomiRNAs Mimicking miR-145-5p, miR-101-3p, and miR-335-5p
by Chiara Papi, Jessica Gasparello, Matteo Zurlo, Lucia Carmela Cosenza, Roberto Gambari and Alessia Finotti
Non-Coding RNA 2023, 9(2), 29; https://doi.org/10.3390/ncrna9020029 - 18 Apr 2023
Cited by 2 | Viewed by 1827
Abstract
(1) Background: MicroRNAs are involved in the expression of the gene encoding the chloride channel CFTR (Cystic Fibrosis Transmembrane Conductance Regulator); the objective of this short report is to study the effects of the treatment of bronchial epithelial Calu-3 cells with molecules mimicking [...] Read more.
(1) Background: MicroRNAs are involved in the expression of the gene encoding the chloride channel CFTR (Cystic Fibrosis Transmembrane Conductance Regulator); the objective of this short report is to study the effects of the treatment of bronchial epithelial Calu-3 cells with molecules mimicking the activity of pre-miR-145-5p, pre-miR-335-5p, and pre-miR-101-3p, and to discuss possible translational applications of these molecules in pre-clinical studies focusing on the development of protocols of possible interest in therapy; (2) Methods: CFTR mRNA was quantified by Reverse Transcription quantitative Polymerase Chain Reaction (RT-qPCR). The production of the CFTR protein was assessed by Western blotting; (3) Results: The treatment of Calu-3 cells with agomiR-145-5p caused the highest inhibition of CFTR mRNA accumulation and CFTR production; (4) Conclusions: The treatment of target cells with the agomiR pre-miR-145-5p should be considered when CFTR gene expression should be inhibited in pathological conditions, such as polycystic kidney disease (PKD), some types of cancer, cholera, and SARS-CoV-2 infection. Full article
(This article belongs to the Special Issue Recent Advances in Chemical Biology to Study and Target ncRNAs)
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10 pages, 271 KiB  
Editorial
The Non-Coding RNA Journal Club: Highlights on Recent Papers—12
by Patrick K. T. Shiu, Mirolyuba Ilieva, Anja Holm, Shizuka Uchida, Johanna K. DiStefano, Agnieszka Bronisz, Ling Yang, Yoh Asahi, Ajay Goel, Liuqing Yang, Ashok Nuthanakanti, Alexander Serganov, Suresh K. Alahari, Chunru Lin, Barbara Pardini, Alessio Naccarati, Jing Jin, Beshoy Armanios, Xiao-bo Zhong, Nikolaos Sideris, Salih Bayraktar, Leandro Castellano, André P. Gerber, He Lin, Simon J. Conn, Doha Magdy Mostafa Sleem and Lisa Timmonsadd Show full author list remove Hide full author list
Non-Coding RNA 2023, 9(2), 28; https://doi.org/10.3390/ncrna9020028 - 18 Apr 2023
Viewed by 2126
Abstract
We are delighted to share with you our twelfth Journal Club and highlight some of the most interesting papers published recently [...] Full article
(This article belongs to the Collection The Non-Coding RNA Journal Club: Highlights on Recent Papers)
31 pages, 1440 KiB  
Review
Targeting miRNAs and Other Non-Coding RNAs as a Therapeutic Approach: An Update
by Emine Bayraktar, Recep Bayraktar, Hulya Oztatlici, Gabriel Lopez-Berestein, Paola Amero and Cristian Rodriguez-Aguayo
Non-Coding RNA 2023, 9(2), 27; https://doi.org/10.3390/ncrna9020027 - 13 Apr 2023
Cited by 21 | Viewed by 2922
Abstract
Since the discovery of the first microRNAs (miRNAs, miRs), the understanding of miRNA biology has expanded substantially. miRNAs are involved and described as master regulators of the major hallmarks of cancer, including cell differentiation, proliferation, survival, the cell cycle, invasion, and metastasis. Experimental [...] Read more.
Since the discovery of the first microRNAs (miRNAs, miRs), the understanding of miRNA biology has expanded substantially. miRNAs are involved and described as master regulators of the major hallmarks of cancer, including cell differentiation, proliferation, survival, the cell cycle, invasion, and metastasis. Experimental data indicate that cancer phenotypes can be modified by targeting miRNA expression, and because miRNAs act as tumor suppressors or oncogenes (oncomiRs), they have emerged as attractive tools and, more importantly, as a new class of targets for drug development in cancer therapeutics. With the use of miRNA mimics or molecules targeting miRNAs (i.e., small-molecule inhibitors such as anti-miRS), these therapeutics have shown promise in preclinical settings. Some miRNA-targeted therapeutics have been extended to clinical development, such as the mimic of miRNA-34 for treating cancer. Here, we discuss insights into the role of miRNAs and other non-coding RNAs in tumorigenesis and resistance and summarize some recent successful systemic delivery approaches and recent developments in miRNAs as targets for anticancer drug development. Furthermore, we provide a comprehensive overview of mimics and inhibitors that are in clinical trials and finally a list of clinical trials based on miRNAs. Full article
(This article belongs to the Special Issue ncRNAs to Target Molecular Pathways)
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22 pages, 968 KiB  
Review
MicroRNAs in Age-Related Proteostasis and Stress Responses
by Latika Matai and Frank J. Slack
Non-Coding RNA 2023, 9(2), 26; https://doi.org/10.3390/ncrna9020026 - 13 Apr 2023
Cited by 5 | Viewed by 2316
Abstract
Aging is associated with the accumulation of damaged and misfolded proteins through a decline in the protein homeostasis (proteostasis) machinery, leading to various age-associated protein misfolding diseases such as Huntington’s or Parkinson’s. The efficiency of cellular stress response pathways also weakens with age, [...] Read more.
Aging is associated with the accumulation of damaged and misfolded proteins through a decline in the protein homeostasis (proteostasis) machinery, leading to various age-associated protein misfolding diseases such as Huntington’s or Parkinson’s. The efficiency of cellular stress response pathways also weakens with age, further contributing to the failure to maintain proteostasis. MicroRNAs (miRNAs or miRs) are a class of small, non-coding RNAs (ncRNAs) that bind target messenger RNAs at their 3′UTR, resulting in the post-transcriptional repression of gene expression. From the discovery of aging roles for lin-4 in C. elegans, the role of numerous miRNAs in controlling the aging process has been uncovered in different organisms. Recent studies have also shown that miRNAs regulate different components of proteostasis machinery as well as cellular response pathways to proteotoxic stress, some of which are very important during aging or in age-related pathologies. Here, we present a review of these findings, highlighting the role of individual miRNAs in age-associated protein folding and degradation across different organisms. We also broadly summarize the relationships between miRNAs and organelle-specific stress response pathways during aging and in various age-associated diseases. Full article
(This article belongs to the Special Issue ncRNAs in Translational Reprogramming)
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15 pages, 22736 KiB  
Article
LncRNA PNKY Is Upregulated in Breast Cancer and Promotes Cell Proliferation and EMT in Breast Cancer Cells
by Forough Hakiminia, Firooz Jannat Alipoor, Mostafa Keshavarz and Malek Hossein Asadi
Non-Coding RNA 2023, 9(2), 25; https://doi.org/10.3390/ncrna9020025 - 06 Apr 2023
Cited by 1 | Viewed by 1954
Abstract
Long non-coding RNAs (lncRNAs) are known to be important regulators in different cellular processes and are implicated in various human diseases. Recently, lncRNA PNKY has been found to be involved in pluripotency and differentiation of embryonic and postnatal neural stem cells (NSCs); however, [...] Read more.
Long non-coding RNAs (lncRNAs) are known to be important regulators in different cellular processes and are implicated in various human diseases. Recently, lncRNA PNKY has been found to be involved in pluripotency and differentiation of embryonic and postnatal neural stem cells (NSCs); however, its expression and function in cancer cells is still unclear. In the present study, we observed the expression of PNKY in various cancer tissues, including brain, breast, colorectal, and prostate cancers. In particular, we demonstrated that lncRNA PNKY was significantly upregulated in breast tumors, especially high-grade tumors. Knock down experiments indicated that the suppression of PNKY in breast cancer cells could restrict their proliferation by promoting apoptosis, senescence, and cell cycle disruption. Moreover, the results demonstrated that PNKY may play a crucial role in the cell migration of breast cancer cells. We further found that PNKY may trigger EMT in breast cancer cells by upregulating miR-150 and restricting the expression of Zeb1 and Snail. This study is the first to provide new evidence on the expression and biological function of PNKY in cancer cells and its potential contribution to tumor growth and metastasis. Full article
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15 pages, 1814 KiB  
Article
Liquid Biopsies Poorly miRror Renal Ischemia-Reperfusion Injury
by Adaysha C. Williams, Vaishali Singh, Pengyuan Liu and Alison J. Kriegel
Non-Coding RNA 2023, 9(2), 24; https://doi.org/10.3390/ncrna9020024 - 01 Apr 2023
Viewed by 1565
Abstract
Acute kidney injury (AKI) is the rapid reduction in renal function. It is often difficult to detect at an early stage. Biofluid microRNAs (miRs) have been proposed as novel biomarkers due to their regulatory role in renal pathophysiology. The goal of this study [...] Read more.
Acute kidney injury (AKI) is the rapid reduction in renal function. It is often difficult to detect at an early stage. Biofluid microRNAs (miRs) have been proposed as novel biomarkers due to their regulatory role in renal pathophysiology. The goal of this study was to determine the overlap in AKI miRNA profiles in the renal cortex, urine, and plasma samples collected from a rat model of ischemia-reperfusion (IR)-induced AKI. Bilateral renal ischemia was induced by clamping the renal pedicles for 30 min, followed by reperfusion. Urine was then collected over 24 h, followed by terminal blood and tissue collection for small RNA profiling. Differentially expressed (IR vs. sham) miRs within the urine and renal cortex sample types demonstrated a strong correlation in normalized abundance regardless of injury (IR and sham: R2 = 0.8710 and 0.9716, respectively). Relatively few miRs were differentially expressed in multiple samples. Further, there were no differentially expressed miRs with clinically relevant sequence conservation common between renal cortex and urine samples. This project highlights the need for a comprehensive analysis of potential miR biomarkers, including analysis of pathological tissues and biofluids, with the goal of identifying the cellular origin of altered miRs. Analysis at earlier timepoints is needed to further evaluate clinical potential. Full article
(This article belongs to the Special Issue Non-coding RNA in the USA: Latest Advances and Perspectives)
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14 pages, 954 KiB  
Review
CircRNAs and RNA-Binding Proteins Involved in the Pathogenesis of Cancers or Central Nervous System Disorders
by Yuka Ikeda, Sae Morikawa, Moeka Nakashima, Sayuri Yoshikawa, Kurumi Taniguchi, Haruka Sawamura, Naoko Suga, Ai Tsuji and Satoru Matsuda
Non-Coding RNA 2023, 9(2), 23; https://doi.org/10.3390/ncrna9020023 - 31 Mar 2023
Cited by 10 | Viewed by 2642
Abstract
Circular RNAs (circRNAs), a newly recognized group of noncoding RNA transcripts, have established widespread attention due to their regulatory role in cell signaling. They are covalently closed noncoding RNAs that form a loop, and are typically generated during the splicing of precursor RNAs. [...] Read more.
Circular RNAs (circRNAs), a newly recognized group of noncoding RNA transcripts, have established widespread attention due to their regulatory role in cell signaling. They are covalently closed noncoding RNAs that form a loop, and are typically generated during the splicing of precursor RNAs. CircRNAs are key post-transcriptional and post-translational regulators of gene expression programs that might influence cellular response and/or function. In particular, circRNAs have been considered to function as sponges of specific miRNA, regulating cellular processes at the post-transcription stage. Accumulating evidence has shown that the aberrant expression of circRNAs could play a key role in the pathogenesis of several diseases. Notably, circRNAs, microRNAs, and several RNA-binding proteins, including the antiproliferative (APRO) family proteins, could be indispensable gene modulators, which might be strongly linked to the occurrence of diseases. In addition, circRNAs have attracted general interest for their stability, abundance in the brain, and their capability to cross the blood–brain barrier. Here, we present the current findings and theragnostic potentials of circRNAs in several diseases. With this, we aim to provide new insights to support the development of novel diagnostic and/or therapeutic strategies for these diseases. Full article
(This article belongs to the Special Issue ncRNAs to Target Molecular Pathways)
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11 pages, 280 KiB  
Article
The Role of Genetic Variants in the Long Non-Coding RNA Genes MALAT1 and H19 in the Pathogenesis of Childhood Obesity
by Tatiana Pavlovna Shkurat, Manar Ammar, Olga Bocharova, Elena Teplyakova, Anzhela Aleksandrova, Ruba Ali and Leonard Lipovich
Non-Coding RNA 2023, 9(2), 22; https://doi.org/10.3390/ncrna9020022 - 30 Mar 2023
Cited by 1 | Viewed by 1768
Abstract
Long non-coding RNAs (lncRNAs) play important roles in the maintenance of metabolic homeostasis. Recently, many studies have suggested that lncRNAs, such as Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and Imprinted Maternally Expressed Transcript (H19), might participate in the pathogenesis of metabolic disorders [...] Read more.
Long non-coding RNAs (lncRNAs) play important roles in the maintenance of metabolic homeostasis. Recently, many studies have suggested that lncRNAs, such as Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1) and Imprinted Maternally Expressed Transcript (H19), might participate in the pathogenesis of metabolic disorders such as obesity. We conducted a case-control study with 150 Russian children and adolescents aged between 5 and 17 years old in order to assess the statistical association between the single nucleotide polymorphisms (SNPs) rs3200401 in MALAT1 and rs217727 in H19, and the risk of developing obesity in this population. We further explored the possible association of rs3200401 and rs217727 with BMI Z-score and insulin resistance. The MALAT1 rs3200401 and H19 rs217727 SNPs were genotyped using Taqman SNP genotyping assay. The MALAT1 rs3200401 SNP was identified as a risk factor for childhood obesity (p < 0.05) under the dominant and allelic models, and the CT heterozygous genotype was associated with the risk of increased BMI and with insulin resistance. The H19 rs217727 SNP had no significant association with obesity risk (all p > 0.05). Our findings thus suggest that MALAT1 SNP rs3200401 is a potential indicator of obesity susceptibility and pathogenesis in children and adolescents. Full article
13 pages, 2539 KiB  
Article
Therapeutic Effects of WT1 Silencing via Respiratory Administration of Neutral DOPC Liposomal-siRNA in a Lung Metastasis Melanoma Murine Model
by Martin R. Ramos-Gonzalez, Eduardo Vazquez-Garza, Gerardo Garcia-Rivas, Cristian Rodriguez-Aguayo and Arturo Chavez-Reyes
Non-Coding RNA 2023, 9(2), 21; https://doi.org/10.3390/ncrna9020021 - 22 Mar 2023
Cited by 1 | Viewed by 1904
Abstract
The lungs represent a frequent target for metastatic melanoma as they offer a high-oxygen environment for tumor development. The overexpression of the WT1 protein has been associated with the occurrence of melanoma. In this study, we evaluated the effects of silencing the WT1 [...] Read more.
The lungs represent a frequent target for metastatic melanoma as they offer a high-oxygen environment for tumor development. The overexpression of the WT1 protein has been associated with the occurrence of melanoma. In this study, we evaluated the effects of silencing the WT1 protein by siRNA in both in vitro in the B16F10 melanoma cell line and in vivo in a murine model of lung metastatic melanoma. We did this by implementing a novel respiratory delivery strategy of a neutral DOPC liposomal-siRNA system (L-siRNA). In vitro studies showed an effective silencing of the WT1 protein in the siRNAs’ WT1-treated cells when compared with controls, resulting in a loss of the cell’s viability and proliferation by inducing G1 arrest, the inhibition of the migration and invasion capacities of the cells, as well as the induction of apoptosis. In vivo, the respiratory administration of L-WT1 siRNA showed an efficient biodistribution on the lungs. After two weeks of treatment, the silencing of the WT1 protein resulted in an important antitumor activity that reduced the tumor weight. In the survival study, L-WT1 treatment could significantly delay the death of the animals. This work demonstrates the efficacy of the L-siRNA respiratory administration as a novel therapy to reduce pulmonary tumors and to increase survivability by silencing specific cancer oncogenes as WT1. Full article
(This article belongs to the Special Issue ncRNAs to Target Molecular Pathways)
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19 pages, 2818 KiB  
Article
Reassessing the Abundance of miRNAs in the Human Pancreas and Rodent Cell Lines and Its Implication
by Guihua Sun, Meirigeng Qi, Alexis S. Kim, Elizabeth M. Lizhar, Olivia W. Sun, Ismail H. Al-Abdullah and Arthur D. Riggs
Non-Coding RNA 2023, 9(2), 20; https://doi.org/10.3390/ncrna9020020 - 17 Mar 2023
Viewed by 1452
Abstract
miRNAs are critical for pancreas development and function. However, we found that there are discrepancies regarding pancreatic miRNA abundance in published datasets. To obtain a more relevant profile that is closer to the true profile, we profiled small RNAs from human islets cells, [...] Read more.
miRNAs are critical for pancreas development and function. However, we found that there are discrepancies regarding pancreatic miRNA abundance in published datasets. To obtain a more relevant profile that is closer to the true profile, we profiled small RNAs from human islets cells, acini, and four rodent pancreatic cell lines routinely used in diabetes and pancreatic research using a bias reduction protocol for small RNA sequencing. In contrast to the previous notion that miR-375-3p is the most abundant pancreatic miRNA, we found that miR-148a-3p and miR-7-5p were also abundant in islets. In silico studies using predicted and validated targets of these three miRNAs revealed that they may work cooperatively in endocrine and exocrine cells. Our results also suggest, compared to the most-studied miR-375, that both miR-148a-3p and miR-7-5p may play more critical roles in the human pancreas. Moreover, according to in silico-predicted targets, we found that miR-375-3p had a much broader target spectrum by targeting the coding sequence and the 5′ untranslated region, rather than the conventional 3′ untranslated region, suggesting additional unexplored roles of miR-375-3p beyond the pancreas. Our study provides a valuable new resource for studying miRNAs in pancreata. Full article
(This article belongs to the Collection Feature Papers in Non-Coding RNA)
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15 pages, 2668 KiB  
Review
Long Noncoding RNA H19: A Novel Oncogene in Liver Cancer
by Yanyan Wang, Jing Zeng, Weidong Chen, Jiangao Fan, Phillip B. Hylemon and Huiping Zhou
Non-Coding RNA 2023, 9(2), 19; https://doi.org/10.3390/ncrna9020019 - 09 Mar 2023
Cited by 8 | Viewed by 2675
Abstract
Liver cancer is the second leading cause of cancer-related death globally, with limited treatment options. Recent studies have demonstrated the critical role of long noncoding RNAs (lncRNAs) in the pathogenesis of liver cancers. Of note, mounting evidence has shown that lncRNA H19, an [...] Read more.
Liver cancer is the second leading cause of cancer-related death globally, with limited treatment options. Recent studies have demonstrated the critical role of long noncoding RNAs (lncRNAs) in the pathogenesis of liver cancers. Of note, mounting evidence has shown that lncRNA H19, an endogenous noncoding single-stranded RNA, functions as an oncogene in the development and progression of liver cancer, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the two most prevalent primary liver tumors in adults. H19 can affect many critical biological processes, including the cell proliferation, apoptosis, invasion, and metastasis of liver cancer by its function on epigenetic modification, H19/miR-675 axis, miRNAs sponge, drug resistance, and its regulation of downstream pathways. In this review, we will focus on the most relevant molecular mechanisms of action and regulation of H19 in the development and pathophysiology of HCC and CCA. This review aims to provide valuable perspectives and translational applications of H19 as a potential diagnostic marker and therapeutic target for liver cancer disease. Full article
(This article belongs to the Special Issue Women’s Special Issue Series: Noncoding RNAs and Diseases)
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15 pages, 889 KiB  
Review
Insights into Online microRNA Bioinformatics Tools
by Diana Luna Buitrago, Ruth C. Lovering and Andrea Caporali
Non-Coding RNA 2023, 9(2), 18; https://doi.org/10.3390/ncrna9020018 - 06 Mar 2023
Cited by 4 | Viewed by 4110
Abstract
MicroRNAs (miRNAs) are members of the small non-coding RNA family regulating gene expression at the post-transcriptional level. MiRNAs have been found to have critical roles in various biological and pathological processes. Research in this field has significantly progressed, with increased recognition of the [...] Read more.
MicroRNAs (miRNAs) are members of the small non-coding RNA family regulating gene expression at the post-transcriptional level. MiRNAs have been found to have critical roles in various biological and pathological processes. Research in this field has significantly progressed, with increased recognition of the importance of miRNA regulation. As a result of the vast data and information available regarding miRNAs, numerous online tools have emerged to address various biological questions related to their function and influence across essential cellular processes. This review includes a brief introduction to available resources for an investigation covering aspects such as miRNA sequences, target prediction/validation, miRNAs associated with disease, pathway analysis and genetic variants within miRNAs. Full article
(This article belongs to the Special Issue Methods and Tools in RNA Biology)
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27 pages, 6331 KiB  
Article
Immunoregulatory Biomarkers of the Remission Phase in Type 1 Diabetes: miR-30d-5p Modulates PD-1 Expression and Regulatory T Cell Expansion
by Laia Gomez-Muñoz, David Perna-Barrull, Marta Murillo, Maria Pilar Armengol, Marta Alcalde, Marti Catala, Silvia Rodriguez-Fernandez, Sergi Sunye, Aina Valls, Jacobo Perez, Raquel Corripio and Marta Vives-Pi
Non-Coding RNA 2023, 9(2), 17; https://doi.org/10.3390/ncrna9020017 - 28 Feb 2023
Cited by 2 | Viewed by 3376
Abstract
The partial remission (PR) phase of type 1 diabetes (T1D) is an underexplored period characterized by endogenous insulin production and downmodulated autoimmunity. To comprehend the mechanisms behind this transitory phase and develop precision medicine strategies, biomarker discovery and patient stratification are unmet needs. [...] Read more.
The partial remission (PR) phase of type 1 diabetes (T1D) is an underexplored period characterized by endogenous insulin production and downmodulated autoimmunity. To comprehend the mechanisms behind this transitory phase and develop precision medicine strategies, biomarker discovery and patient stratification are unmet needs. MicroRNAs (miRNAs) are small RNA molecules that negatively regulate gene expression and modulate several biological processes, functioning as biomarkers for many diseases. Here, we identify and validate a unique miRNA signature during PR in pediatric patients with T1D by employing small RNA sequencing and RT-qPCR. These miRNAs were mainly related to the immune system, metabolism, stress, and apoptosis pathways. The implication in autoimmunity of the most dysregulated miRNA, miR-30d-5p, was evaluated in vivo in the non-obese diabetic mouse. MiR-30d-5p inhibition resulted in increased regulatory T cell percentages in the pancreatic lymph nodes together with a higher expression of CD200. In the spleen, a decrease in PD-1+ T lymphocytes and reduced PDCD1 expression were observed. Moreover, miR-30d-5p inhibition led to an increased islet leukocytic infiltrate and changes in both effector and memory T lymphocytes. In conclusion, the miRNA signature found during PR shows new putative biomarkers and highlights the immunomodulatory role of miR-30d-5p, elucidating the processes driving this phase. Full article
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