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Chronic kidney disease (CKD) is a leading cause of morbidity and mortality globally. Maternal obesity during pregnancy is linked to systemic inflammation and elevated levels of the pro-inflammatory cytokine interleukin-6 (IL-6). In our previous work, we demonstrated that increased maternal IL-6 during gestation impacts intrauterine development in mice. We hypothesized that IL-6-induced inflammation alters gene expression in the developing fetus. To test this, pregnant mice were administered IL-6 or saline during mid-gestation. Newborn mouse kidneys were analyzed using mRNA-seq, miRNA-seq and whole-genome bisulfite-seq (WGBS). A multi-omics approach was employed to quantify mRNA gene expression, miRNA expression and DNA methylation, using advanced bioinformatics and data integration techniques. Our analysis identified 19 key genes present in multiple omics datasets, regulated by epigenetics and miRNAs. We constructed a regulatory network for these genes, revealing disruptions in pathways such as Mannose type O-glycan biosynthesis, the cell cycle, apoptosis and FoxO signaling. Notably, the Atp7b gene was regulated by DNA methylation and miR-223 targeting, whereas the Man2a1 gene was controlled by DNA methylation affecting energy metabolism. These findings suggest that these genes may play a role in fetal programming, potentially leading to CKD later in life due to gestational inflammation. [ABSTRACT FROM AUTHOR]

Presbycusis, also referred to as age-related hearing loss (ARHL), is a multifaceted condition caused by the natural aging process affecting the auditory system. Genome-wide association studies (GWAS) in human populations can identify potential genes linked to ARHL. Despite this, our knowledge of the biochemical and molecular mechanisms behind the condition remains incomplete. This study aims to evaluate a potential protective tool for ARHL treatment by comparing human blood-based target gene-miRNA associations regulated in ARHL. To identify promising target genes for ARHL, we utilized an mRNA assay. To determine the role of miRNA in ARHL, we investigated the expression profile of miRNA in whole blood in ARHL patients with real-time polymerase chain reaction (RT-qPCR). A reporter gene assay was performed to confirm the regulation of candidate genes by microRNA. Through RT-qPCR validation analysis, we finally confirmed the relationship between ARHL and the role of the interferon-gamma (IFNG) gene. This gene can be regarded as an age-related gene. Through gene ontology (GO) analysis, it has been found that these genes are enriched in pathways related to apoptosis. Among them, IFNG induces an inflammatory response, apoptotic cell death, and cellular senescence. We found that miR-409-3p downregulates the expression of the IFNG in vitro. In addition, the downregulation of the IFNG by miRNA 409-3p promoted cell apoptosis and suppressed proliferation. In conclusion, our study produced gene signatures and associated microRNA regulation that could be a protective key for ARHL patients. IFNG genes and miR-409-3p should be investigated for their usefulness as a new biomarker for treatment modality. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) have emerged as pivotal regulators of gene expression with diverse roles in various biological processes. In recent years, research into circRNAs' involvement in bone biology has gained significant attention, unveiling their potential as novel regulators and biomarkers in bone-related disorders and diseases. CircRNAs, characterized by their closed-loop structure, exhibit stability and resistance to degradation, underscoring their functional significance. In bone tissue, circRNAs are involved in critical processes such as osteogenic differentiation, osteoclastogenesis, and bone remodeling through intricate molecular mechanisms including microRNA regulation. Dysregulated circRNAs are associated with various bone disorders, suggesting their potential as diagnostic and prognostic biomarkers. The therapeutic targeting of these circRNAs holds promise for addressing bone-related conditions, offering new perspectives for precision medicine. Thus, circRNAs constitute integral components of bone regulatory networks, impacting both physiological bone homeostasis and pathological conditions. This review provides a comprehensive overview of circRNAs in bone biology, emphasizing their regulatory mechanisms, functional implications, and therapeutic potential. [ABSTRACT FROM AUTHOR]

The development of obesity is associated with substantial modulation of adipose tissue (AT) structure. The plasticity of the AT is reflected by its remarkable ability to expand or reduce in size throughout the adult lifespan, which is linked to the development of its vasculature. This increase in AT vasculature could be mediated by the differentiation of adipose tissue-derived stem cells (ASCs) into endothelial cells (ECs) and form new microvasculature. We have already shown that microRNA (miRNA)-145 regulates the differentiation of ASCs into EC-like (ECL) cells. Here, we investigated whether ASCs-differentiation into ECs is governed by a miRNAs signature that depends on fat depot location and /or the metabolic condition produced by obesity. Human ASCs, which were obtained from white AT by surgical procedures from lean and obese patients, were induced to differentiate into ECL cells. We have identified that miRNA-29b-3p in both subcutaneous (s)ASCs and visceral ASCs and miRNA-424-5p and miRNA-378a-3p in subcutaneous (s)ASCs are involved in differentiation into EC-like cells. These miRNAs modulate their pro-angiogenic effects on ASCs by targeting FGFR1, NRP2, MAPK1, and TGF-β2, and the MAPK signaling pathway. We show for the first time that miRNA-29b-3p upregulation contributes to ASCs' differentiation into ECL cells by directly targeting TGFB2 in both sASCs and visceral ASCs. Moreover, our results reveal that, independent of sASCs' origin (obese/lean), the upregulation of miRNA-378a-3p and the downregulation of miRNA-424-5p inhibit MAPK1 and overexpress FGFR1 and NRP2, respectively. In summary, both the adipose depot location and obesity affect the differentiation of resident ASCs through the expression of specific miRNAs. [ABSTRACT FROM AUTHOR]

Non-healing lesions in diabetic foot ulcers are a significant effect of poor angiogenesis. Epigenetic regulators, mainly lncRNA and miRNA, are recognized for their important roles in disease progression. We deciphered the regulation of lncRNA NEAT1 through the miR-146a-5p/mafG axis in the progression of DFU. A lowered expression of lncRNA NEAT1 was associated with dysregulated angiogenesis through the reduced expression of mafG, SDF-1α, and VEGF in chronic ulcer subjects compared to acute DFU. This was validated by silencing NEAT1 by SiRNA in the endothelial cells which resulted in the transcriptional repression of target genes. Our in silico analysis identified miR-146a-5p as a potential target of lncRNA NEAT1. Further, silencing NEAT1 led to an increase in the levels of miR-146a-5p in chronic DFU subjects. This research presents the role of the lncRNA NEAT1/miR-146a-5p/mafG axis in enhancing angiogenesis in DFU. [ABSTRACT FROM AUTHOR]

Base excision repair (BER) is the predominant pathway for the removal of most forms of hydrolytic, oxidative, and alkylative DNA lesions. The precise functioning of BER is achieved via the regulation of each step by regulatory/accessory proteins, with the most important of them being poly(ADP-ribose) polymerase 1 (PARP1). PARP1′s regulatory functions extend to many cellular processes including the regulation of mRNA stability and decay. PARP1 can therefore affect BER both at the level of BER proteins and at the level of their mRNAs. Systematic data on how the PARP1 content affects the activities of key BER proteins and the levels of their mRNAs in human cells are extremely limited. In this study, a CRISPR/Cas9-based technique was used to knock out the PARP1 gene in the human HEK 293FT line. The obtained cell clones with the putative PARP1 deletion were characterized by several approaches including PCR analysis of deletions in genomic DNA, Sanger sequencing of genomic DNA, quantitative PCR analysis of PARP1 mRNA, Western blot analysis of whole-cell-extract (WCE) proteins with anti-PARP1 antibodies, and PAR synthesis in WCEs. A quantitative PCR analysis of mRNAs coding for BER-related proteins—PARP2, uracil DNA glycosylase 2, apurinic/apyrimidinic endonuclease 1, DNA polymerase β, DNA ligase III, and XRCC1—did not reveal a notable influence of the PARP1 knockout. The corresponding WCE catalytic activities evaluated in parallel did not differ significantly between the mutant and parental cell lines. No noticeable effect of poly(ADP-ribose) synthesis on the activity of the above WCE enzymes was revealed either. [ABSTRACT FROM AUTHOR]

Overcoming senescence with tissue engineering has a promising impact on multiple diseases. Here, we provide an overview of recent studies in which cellular senescence was inhibited through the up/downregulation of specific lncRNAs. This approach prevented senescence in the bones, joints, nervous system, heart, and blood vessels, with a potential impact on regeneration and the prevention of osteoarthritis and osteoporosis, as well as neurodegenerative and cardiovascular diseases. Senescence of the skin and liver could also be prevented through the regulation of cellular levels of specific lncRNAs, resulting in the rejuvenation of cells from these organs and their potential protection from disease. From these exciting achievements, which support tissue regeneration and are not restricted to stem cells, we propose lncRNA regulation through RNA or gene therapies as a prospective preventive and therapeutic approach against aging and multiple aging-related diseases. [ABSTRACT FROM AUTHOR]

It is now widely recognized that mesenchymal stem cells (MSCs) possess the capacity to differentiate into a wide array of cell types. Numerous studies have identified the role of lncRNA in the regulation of MSC differentiation. It is important to elucidate the role and interplay of microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) in the regulation of signalling pathways that govern MSC function. Furthermore, miRNAs and lncRNAs are important clinical for innovative strategies aimed at addressing a wide spectrum of existing and emerging disease. Hence it is important to consider their impact on MSC function and differentiation. Examining the data available in public databases, we have collected the literature containing the latest discoveries pertaining to human stem cells and their potential in both fundamental research and clinical applications. Furthermore, we have compiled completed clinical studies that revolve around the application of MSCs, shedding light on the opportunities presented by harnessing the regulatory potential of miRNAs and lncRNAs. This exploration of the therapeutic possibilities offered by miRNAs and lncRNAs within MSCs unveils exciting prospects for the development of precision therapies and personalized treatment approaches. Ultimately, these advancements promise to augment the efficacy of regenerative strategies and produce positive outcomes for patients. As research in this field continues to evolve, it is imperative to explore and exploit the vast potential of miRNAs and lncRNAs as therapeutic agents. The findings provide a solid basis for ongoing investigations, fuelling the quest to fully unlock the regenerative potential of MSCs. [ABSTRACT FROM AUTHOR]

Fused-in sarcoma (FUS) gene mutations have been implicated in amyotrophic lateral sclerosis (ALS). This study aimed to investigate the impact of FUS mutations (R521H and P525L) on the transcriptome of induced pluripotent stem cells (iPSCs) and iPSC-derived motor neurons (iMNs). Using RNA sequencing (RNA Seq), we characterized differentially expressed genes (DEGs) and differentially expressed lncRNAs (DELs) and subsequently predicted lncRNA–mRNA target pairs (TAR pairs). Our results show that FUS mutations significantly altered the expression profiles of mRNAs and lncRNAs in iPSCs. Using this large dataset, we identified and verified six key differentially regulated TAR pairs in iPSCs that were also altered in iMNs. These target transcripts included: GPR149, NR4A, LMO3, SLC15A4, ZNF404, and CRACD. These findings indicated that selected mutant FUS-induced transcriptional alterations persist from iPSCs into differentiated iMNs. Functional enrichment analyses of DEGs indicated pathways associated with neuronal development and carcinogenesis as likely altered by these FUS mutations. Furthermore, ingenuity pathway analysis (IPA) and GO network analysis of lncRNA-targeted mRNAs indicated associations between RNA metabolism, lncRNA regulation, and DNA damage repair. Our findings provide insights into potential molecular mechanisms underlying the pathophysiology of ALS-associated FUS mutations and suggest potential therapeutic targets for the treatment of ALS. [ABSTRACT FROM AUTHOR]

Advances in RNA-sequencing technologies have led to the identification of molecular biomarkers for several diseases, including neurodegenerative diseases, such as Alzheimer's, Parkinson's, Huntington's diseases and Amyotrophic Lateral Sclerosis. Despite the nature of glaucoma as a neurodegenerative disorder with several similarities with the other above-mentioned diseases, transcriptional data about this disease are still scarce. microRNAs are small molecules (~17–25 nucleotides) that have been found to be specifically expressed in the CNS as major components of the system regulating the development signatures of neurodegenerative diseases and the homeostasis of the brain. In this review, we sought to identify similarities between the functional mechanisms and the activated pathways of the most common neurodegenerative diseases, as well as to discuss how those mechanisms are regulated by miRNAs, using RNA-Seq as an approach to compare them. We also discuss therapeutically suitable applications for these disease hallmarks in clinical future studies. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are important regulators of embryonic stem cell (ESC) biology, and their study has identified key regulatory mechanisms. To find novel pathways regulated by miRNAs in ESCs, we undertook a bioinformatics analysis of gene pathways differently expressed in the absence of miRNAs due to the deletion of Dicer, which encodes an RNase that is essential for the synthesis of miRNAs. One pathway that stood out was Ca2+ signaling. Interestingly, we found that Dicer−/− ESCs had no difference in basal cytoplasmic Ca2+ levels but were hyperresponsive when Ca2+ import into the endoplasmic reticulum (ER) was blocked by thapsigargin. Remarkably, the increased Ca2+ response to thapsigargin in ESCs resulted in almost no increase in apoptosis and no differences in stress response pathways, despite the importance of miRNAs in the stress response of other cell types. The increased Ca2+ response in Dicer−/− ESCs was also observed during purinergic receptor activation, demonstrating a physiological role for the miRNA regulation of Ca2+ signaling pathways. In examining the mechanism of increased Ca2+ responsiveness to thapsigargin, neither store-operated Ca2+ entry nor Ca2+ clearance mechanisms from the cytoplasm appeared to be involved. Rather, it appeared to involve an increase in the expression of one isoform of the IP3 receptors (Itpr2). miRNA regulation of Itpr2 expression primarily appeared to be indirect, with transcriptional regulation playing a major role. Therefore, the miRNA regulation of Itpr2 expression offers a unique mechanism to regulate Ca2+ signaling pathways in the physiology of pluripotent stem cells. [ABSTRACT FROM AUTHOR]

The mammalian Ccr4–Not complex, carbon catabolite repression 4 (Ccr4)-negative on TATA-less (Not), is a large, highly conserved, multifunctional assembly of proteins that acts at different cellular levels to regulate gene expression. It is involved in the control of the cell cycle, chromatin modification, activation and inhibition of transcription initiation, control of transcription elongation, RNA export, and nuclear RNA surveillance; the Ccr4–Not complex also plays a central role in the regulation of mRNA decay. Growing evidence suggests that gene transcription has a vital role in shaping the landscape of genome replication and is also a potent source of replication stress and genome instability. Here, we have examined the effects of the inactivation of the Ccr4–Not complex, via the depletion of the scaffold subunit CNOT1, on DNA replication and genome integrity in mammalian cells. In CNOT1-depleted cells, the elevated expression of the general transcription factor TATA-box binding protein (TBP) leads to increased RNA synthesis, which, together with R-loop accumulation, results in replication fork slowing, DNA damage, and senescence. Furthermore, we have shown that the stability of TBP mRNA increases in the absence of CNOT1, which may explain its elevated protein expression in CNOT1-depleted cells. Finally, we have shown the activation of mitogen-activated protein kinase signalling as evidenced by ERK1/2 phosphorylation in the absence of CNOT1, which may be responsible for the observed cell cycle arrest at the border of G1/S. [ABSTRACT FROM AUTHOR]

Background: Asthmatic patients' responses to inhaled corticosteroids (ICS) are variable and difficult to quantify. We have previously defined a Cross-sectional Asthma STEroid Response (CASTER) measure of ICS response. MicroRNAs (miRNAs) have shown strong effects on asthma and inflammatory processes. Objective: The purpose of this study was to identify key associations between circulating miRNAs and ICS response in childhood asthma. Methods: Small RNA sequencing in peripheral blood serum from 580 children with asthma on ICS treatment from The Genetics of Asthma in Costa Rica Study (GACRS) was used to identify miRNAs associated with ICS response using generalized linear models. Replication was conducted in children on ICS from the Childhood Asthma Management Program (CAMP) cohort. The association between replicated miRNAs and the transcriptome of lymphoblastoid cell lines in response to a glucocorticoid was assessed. Results: The association study on the GACRS cohort identified 36 miRNAs associated with ICS response at 10% false discovery rate (FDR), three of which (miR-28-5p, miR-339-3p, and miR-432-5p) were in the same direction of effect and significant in the CAMP replication cohort. In addition, in vitro steroid response lymphoblastoid gene expression analysis revealed 22 dexamethasone responsive genes were significantly associated with three replicated miRNAs. Furthermore, Weighted Gene Co-expression Network Analysis (WGCNA) revealed a significant association between miR-339-3p and two modules (black and magenta) of genes associated with immune response and inflammation pathways. Conclusion: This study highlighted significant association between circulating miRNAs miR-28-5p, miR-339-3p, and miR-432-5p and ICS response. miR-339-3p may be involved in immune dysregulation, which leads to a poor response to ICS treatment. [ABSTRACT FROM AUTHOR]

Defects in the development of the ocular lens can cause congenital cataracts. To understand the various etiologies of congenital cataracts, it is important to characterize the genes linked to this developmental defect and to define their downstream pathways that are relevant to lens biology and pathology. Deficiency or alteration of several RNA-binding proteins, including the conserved RBP Celf1 (CUGBP Elav-like family member 1), has been described to cause lens defects and early onset cataracts in animal models and/or humans. Celf1 is involved in various aspects of post-transcriptional gene expression control, including regulation of mRNA stability/decay, alternative splicing and translation. Celf1 germline knockout mice and lens conditional knockout (Celf1cKO) mice develop fully penetrant cataracts in early postnatal stages. To define the genome-level changes in RNA transcripts that result from Celf1 deficiency, we performed high-throughput RNA-sequencing of Celf1cKO mouse lenses at postnatal day (P) 0. Celf1cKO lenses exhibit 987 differentially expressed genes (DEGs) at cut-offs of >1.0 log2 counts per million (CPM), ≥±0.58 log2 fold-change and <0.05 false discovery rate (FDR). Of these, 327 RNAs were reduced while 660 were elevated in Celf1cKO lenses. The DEGs were subjected to various downstream analyses including iSyTE lens enriched-expression, presence in Cat-map, and gene ontology (GO) and representation of regulatory pathways. Further, a comparative analysis was done with previously generated microarray datasets on Celf1cKO lenses P0 and P6. Together, these analyses validated and prioritized several key genes mis-expressed in Celf1cKO lenses that are relevant to lens biology, including known cataract-linked genes (e.g., Cryab, Cryba2, Cryba4, Crybb1, Crybb2, Cryga, Crygb, Crygc, Crygd, Cryge, Crygf, Dnase2b, Bfsp1, Gja3, Pxdn, Sparc, Tdrd7, etc.) as well as novel candidates (e.g., Ell2 and Prdm16). Together, these data have defined the alterations in lens transcriptome caused by Celf1 deficiency, in turn uncovering downstream genes and pathways (e.g., structural constituents of eye lenses, lens fiber cell differentiation, etc.) associated with lens development and early-onset cataracts. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) is a more aggressive type of breast cancer due to its heterogeneity and complex molecular mechanisms. TNBC has a high risk for metastasis, and it is difficult to manage clinical conditions of the patients. Various investigations are being conducted to overcome these challenges using RNA, DNA, and proteins for early diagnosis and treatment. Recently, long non-coding RNAs (lncRNAs) have emerged as a novel target to treat the multistep process of TNBC. LncRNAs regulate epigenetic expression levels, cell proliferation and apoptosis, and tumour invasiveness and metastasis. Thus, lncRNA-based early diagnosis and treatment options could be helpful, especially for patients with severe TNBC. lncRNAs are expressed in a highly specific manner in cells and tissues and are involved in TNBC progression and development. lncRNAs could be used as sensitive and specific targets for diagnosis, treatment, and monitoring of patients with TNBC. Therefore, the exploration of novel diagnostic and prognostic biomarkers is of extreme importance. Here, we discuss the molecular advances on lncRNA regulation of TNBC and lncRNA-based early diagnosis, treatment, and drug resistance. [ABSTRACT FROM AUTHOR]

The existence of circular RNA (circRNA) research in mainstream science can be attributed to the contemporary synergism of big data and keen attention to detail by several research groups worldwide. Since the re-emergence of these non-canonical RNA transcripts, seminal advances have been made in understanding their biogenesis, interactome, and functions in diverse fields and a myriad of human diseases. However, most research outputs to date have focused on the ability of highly stable circRNAs to interact with, and impact signalling through, microRNAs. This is likely to be the result of seminal papers in the field ascribing a few remarkable circRNAs as "miRNA sponges". However, the stoichiometric ratio between the (often-lowly-expressed) circRNA and their (commonly-more-abundant) target is rarely in favour of a biologically relevant and functional consequence of these interactions. It is time for yet another revolution in circRNA research to uncover functions beyond their documented ability to bind miRNAs. This Special Issue aims to highlight non-canonical functions for this non-canonical family of RNA molecules. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are versatile, post-transcriptional regulators of gene expression. Canonical miRNAs are generated through the two-step DROSHA- and DICER-mediated processing of primary miRNA (pri-miRNA) transcripts with optimal or suboptimal features for DROSHA and DICER cleavage and loading into Argonaute (AGO) proteins, whereas multiple hairpin-structured RNAs are encoded in the genome and could be a source of non-canonical miRNAs. Recent advances in miRNA biogenesis research have revealed details of the structural basis of miRNA processing and cluster assistance mechanisms that facilitate the processing of suboptimal hairpins encoded together with optimal hairpins in polycistronic pri-miRNAs. In addition, a deeper investigation of miRNA–target interaction has provided insights into the complexity of target recognition with distinct outcomes, including target-mediated miRNA degradation (TDMD) and cooperation in target regulation by multiple miRNAs. Therefore, the coordinated or network regulation of both miRNA biogenesis and miRNA–target interaction is prevalent in miRNA biology. Alongside recent advances in the mechanistic investigation of miRNA functions, this review summarizes recent findings regarding the ordered regulation of miRNA biogenesis and miRNA–target interaction. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) are recently discovered genetic regulatory molecules that regulate immune responses and are closely associated with the occurrence and development of various diseases, including inflammation, in humans and animals. Under specific physiological conditions, lncRNA expression varies at the cell or tissue level, and lncRNAs can bind to specific miRNAs, target mRNAs, and target proteins to participate in certain processes, such as cell differentiation and inflammatory responses, via the corresponding signaling pathways. This review article summarizes the regulatory role of lncRNAs in macrophage polarization, dendritic cell differentiation, T cell differentiation, and endothelial and epithelial inflammation. In addition, it describes the molecular mechanism of lncRNAs in acute kidney injury, hepatitis, inflammatory injury of the lung, osteoarthritis, mastitis, and neuroinflammation to provide a reference for the molecular regulatory network as well as the genetic diagnosis and treatment of inflammatory diseases in humans and animals. [ABSTRACT FROM AUTHOR]

Over the past two decades, cancer stem cells (CSCs) have emerged as an immensely studied and experimental topic, however a wide range of questions concerning the topic still remain unanswered; in particular, the mechanisms underlying the regulation of tumor stem cells and their characteristics. Understanding the cancer stem-cell signaling pathways may pave the way towards a better comprehension of these mechanisms. Signaling pathways such as WNT, STAT, Hedgehog, NOTCH, PI3K/AKT/mTOR, TGF-β, and NF-κB are responsible not only for modulating various features of CSCs but also their microenvironments. Recently, the prominent roles of various non-coding RNAs such as small non-coding RNAs (sncRNAs) and long non-coding RNAs (lncRNAs) in developing and enhancing the tumor phenotypes have been unfolded. This review attempts to shed light on understanding the influence of long non- coding RNAs in the modulation of various CSC-signaling pathways and its impact on the CSCs and tumor properties; highlighting the protagonistic and antagonistic roles of lncRNAs. [ABSTRACT FROM AUTHOR]

Pine wilt disease (PWD) is a severe environmental problem in Eastern Asia and Western Europe, devastating large forest areas and causing significant economic losses. This disease is caused by the pine wood nematode (PWN), Bursaphelenchus xylophilus, a parasitic migratory nematode that infects the stem of conifer trees. Here we review what is currently known about the molecular defense response in pine trees after infection with PWN, focusing on common responses in different species. By giving particular emphasis to resistance mechanisms reported for selected varieties and families, we identified shared genes and pathways associated with resistance, including the activation of oxidative stress response, cell wall lignification, and biosynthesis of terpenoids and phenylpropanoids. The role of post-transcriptional regulation by small RNAs in pine response to PWN infection is also discussed, as well as the possible implementation of innovative RNA-interference technologies, with a focus on trans-kingdom small RNAs. Finally, the defense response induced by elicitors applied to pine plants before PWN infection to prompt resistance is reviewed. Perspectives about the impact of these findings and future research approaches are discussed. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are widely present in many organisms and regulate the expression of genes in various biological processes such as cell differentiation, metabolism, and development. Numerous studies have shown that miRNAs are abnormally expressed in tumor tissues and are closely associated with tumorigenesis. MiRNA-based cancer gene therapy has consistently shown promising anti-tumor effects and is recognized as a new field in cancer treatment. So far, some clinical trials involving the treatment of malignancies have been carried out; however, studies of miRNA-based cancer gene therapy are still proceeding slowly. Therefore, furthering our understanding of the regulatory mechanisms of miRNA can bring substantial benefits to the development of miRNA-based gene therapy or other combination therapies and the clinical outcome of patients with cancer. Recent studies have revealed that the aberrant expression of miRNA in tumors is associated with promoter sequence mutation, epigenetic alteration, aberrant RNA modification, etc., showing the complexity of aberrant expression mechanisms of miRNA in tumors. In this paper, we systematically summarized the regulation mechanisms of miRNA expression in tumors, with the aim of providing assistance in the subsequent elucidation of the role of miRNA in tumorigenesis and the development of new strategies for tumor prevention and treatment. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) and long non-coding RNA (lncRNA) have been associated with cancer prognosis and the effect of immunotherapy. However, the roles of m6A-related lncRNAs in the prognosis and immunotherapy in lung adenocarcinoma (LUAD) patients remain unclear. We evaluated the m6A modification patterns of 695 samples based on m6A regulators, and prognostic m6A-related lncRNAs were identified via a weighted gene co-expression network analysis. Twelve abnormal m6A regulators and nine prognostic lncRNAs were identified. The tumor microenvironment cell-infiltrating characteristics of three m6A-related lncRNA clusters were highly consistent with the three immune phenotypes of tumors, including immune-excluded, immune-inflamed and immune-desert phenotypes. The lncRNA score system was established, and high lncRNA score patients were associated with better overall survival. The lncRNA score was correlated with the expression of the immune checkpoints. Two immunotherapy cohorts supported that the high lncRNA score enhanced the response to anti-PD-1/L1 immunotherapy and was remarkably correlated with the inflamed immune phenotype, showing significant therapeutic advantages and clinical benefits. Furthermore, the patients with high lncRNA scores were more sensitive to erlotinib and axitinib. The lncRNA score was associated with the expression of miRNA and the regulation of post-transcription. We constructed an applied lncRNA score-system to identify eligible LUAD patients for immunotherapy and predict the sensitivity to chemotherapeutic drugs. [ABSTRACT FROM AUTHOR]

Leydig cells (LCs) are the predominant cells of androgen production, which plays key roles in spermatogenesis and maintaining male secondary sexual characteristics. Abnormal development of LCs affects androgen levels in vivo, affects fertility and may even lead to infertility. Little is known about the regulation mechanism on LCs' development and maturation in domestic animals, especially the regulation of non-coding RNAs. In this study, we continued to dig deeper in the previous RNA-seq data of porcine LCs from our group, combined with detecting the expression profiles in different tissues and different types of cells in the testis, to screen out candidate microRNAs (miRNAs) that may affect the regulation of LCs. A total of two miRNAs, ssc-miR-21-5p and ssc-miR-615 ("ssc" is omitted below), were finally determined. After overexpression and interference of miRNAs in vitro, the effects of candidate miRNAs on the proliferation and apoptosis of TM3 (mouse Leydig cell line) were explored. The results showed that miR-21-5p led to a decrease in TM3 cell density and p53 (apoptosis related protein) expression. Meanwhile, miR-21-5p decreased EdU positive cell numbers, but increased TUNEL positive cell numbers, suggesting miR-21-5p could inhibit proliferation and promote apoptosis. Conversely, miR-615 could increase TM3 cell density. Western blot and TUNEL assay indicated miR-615 inhibited apoptosis, but had no effect on proliferation. In addition, Sox5 was identified a potential target gene of these two miRNAs by Dual-Luciferase reporter system assay. Our findings about functions of miRNAs in TM3 and the mapping of miRNAs-target gene regulatory network would provide an important basis for the further elucidation of miRNAs in regulating pig LCs. [ABSTRACT FROM AUTHOR]

Consistently, the high metastasis of cancer cells is the bottleneck in the process of tumor treatment. In this process of metastasis, a pivotal role is executed by epithelial–mesenchymal transition (EMT). The epithelial-to-mesenchymal transformation was first proposed to occur during embryonic development. Later, its important role in explaining embryonic developmental processes was widely reported. Recently, EMT and its intermediate state were also identified as crucial drivers in tumor progression with the gradual deepening of research. To gain insights into the potential mechanism, increasing attention has been focused on the EMT-related transcription factors. Correspondingly, miRNAs target transcription factors to control the EMT process of tumor cells in different types of cancers, while there are still many exciting and challenging questions about the phenomenon of microRNA regulation of cancer EMT. We describe the relevant mechanisms of miRNAs regulating EMT, and trace the regulatory roles and functions of major EMT-related transcription factors, including Snail, Twist, zinc finger E-box-binding homeobox (ZEB), and other families. In addition, on the basis of the complex regulatory network, we hope that the exploration of the regulatory relationship of non-transcription factors will provide a better understanding of EMT and cancer metastasis. The identification of the mechanism leading to the activation of EMT programs during diverse disease processes also provides a new protocol for the plasticity of distinct cellular phenotypes and possible therapeutic interventions. Here, we summarize the recent progress in this direction, with a promising path for further insight into this fast-moving field. [ABSTRACT FROM AUTHOR]

The GLI-Similar 1-3 (GLIS1-3) genes, in addition to encoding GLIS1-3 Krüppel-like zinc finger transcription factors, also generate circular GLIS (circGLIS) RNAs. GLIS1-3 regulate gene transcription by binding to GLIS binding sites in target genes, whereas circGLIS RNAs largely act as miRNA sponges. GLIS1-3 play a critical role in the regulation of many biological processes and have been implicated in various pathologies. GLIS protein activities appear to be regulated by primary cilium-dependent and -independent signaling pathways that via post-translational modifications may cause changes in the subcellular localization, proteolytic processing, and protein interactions. These modifications can affect the transcriptional activity of GLIS proteins and, consequently, the biological functions they regulate as well as their roles in disease. Recent studies have implicated GLIS1-3 proteins and circGLIS RNAs in the regulation of stemness, self-renewal, epithelial-mesenchymal transition (EMT), cell reprogramming, lineage determination, and differentiation. These biological processes are interconnected and play a critical role in embryonic development, tissue homeostasis, and cell plasticity. Dysregulation of these processes are part of many pathologies. This review provides an update on our current knowledge of the roles GLIS proteins and circGLIS RNAs in the control of these biological processes in relation to their regulation of normal physiological functions and disease. [ABSTRACT FROM AUTHOR]

Post-transcriptional control of gene expression is one important mechanism that enables stringent and rapid modulation of cytokine, chemokines or growth factors expression, all relevant for immune or tumor cell function and communication. The RNA-binding protein KH-type splicing regulatory protein (KSRP) controls the mRNA stability of according genes by initiation of mRNA decay and inhibition of translation, and by enhancing the maturation of microRNAs. Therefore, KSRP plays a pivotal role in immune cell function and tumor progression. In this review, we summarize the current knowledge about KSRP with regard to the regulation of immunologically relevant targets, and the functional role of KSRP on immune responses and tumorigenesis. KSRP is involved in the control of myeloid hematopoiesis. Further, KSRP-mediated mRNA decay of pro-inflammatory factors is necessary to keep immune homeostasis. In case of infection, functional impairment of KSRP is important for the induction of robust immune responses. In this regard, KSRP seems to primarily dampen T helper cell 2 immune responses. In cancer, KSRP has often been associated with tumor growth and metastasis. In summary, aside of initiation of mRNA decay, the KSRP-mediated regulation of microRNA maturation seems to be especially important for its diverse biological functions, which warrants further in-depth examination. [ABSTRACT FROM AUTHOR]

Steroid-induced glaucoma (SIG) is the most common adverse steroid-related effect on the eyes. SIG patients can suffer from trabecular meshwork (TM) dysfunction, intraocular pressure (IOP) elevation, and irreversible vision loss. Previous studies have mainly focused on the role of extracellular matrix turnover in TM dysfunction; however, whether the cellular effects of TM cells are involved in the pathogenesis of SIG remains unclear. Here, we found that the induction of cellular senescence was associated with TM dysfunction, causing SIG in cultured cells and mouse models. Especially, we established the transcriptome landscape in the TM tissue of SIG mice via microarray screening and identified ANRIL as the most differentially expressed long non-coding RNA, with a 5.4-fold change. The expression level of ANRIL was closely related to ocular manifestations (IOP elevation, cup/disc ratio, and retinal nerve fiber layer thickness). Furthermore, p15, the molecular target of ANRIL, was significantly upregulated in SIG and was correlated with ocular manifestations in an opposite direction to ANRIL. The reciprocal regulation between ANRIL and p15 was validated using luciferase reporter assay. Through depletion in cultured cells and a mouse model, ANRIL/p15 signaling was confirmed in cellular senescence via cyclin-dependent kinase activity and, subsequently, by phosphorylation of the retinoblastoma protein. ANRIL depletion imitated the SIG phenotype, most importantly IOP elevation. ANRIL depletion-induced IOP elevation in mice can be effectively suppressed by p15 depletion. Analyses of the single-cell atlas and transcriptome dynamics of human TM tissue showed that ANRIL/p15 expression is spatially enriched in human TM cells and is correlated with TM dysfunction. Moreover, ANRIL is colocalized with a GWAS risk variant (rs944800) of glaucoma, suggesting its potential role underlying genetic susceptibility of glaucoma. Together, our findings suggested that steroid treatment promoted cellular senescence, which caused TM dysfunction, IOP elevation, and irreversible vision loss. Molecular therapy targeting the ANRIL/p15 signal exerted a protective effect against steroid treatment and shed new light on glaucoma management. [ABSTRACT FROM AUTHOR]

Autophagy is a highly conserved multistep lysosomal degradation process in which cellular components are localized to autophagosomes, which subsequently fuse with lysosomes to degrade the sequestered contents. Autophagy serves to maintain cellular homeostasis. There is a close relationship between autophagy and tumor progression, which provides opportunities for the development of anticancer therapeutics that target the autophagy pathway. In this review, we analyze the effects of human papillomavirus (HPV) E5, E6, and E7 oncoproteins on autophagy processes in cervical cancer development. Inhibition of the expression or the activity of E5, E6, and E7 can induce autophagy in cells expressing HPV oncogenes. Thus, E5, E6, and E7 oncoproteins target autophagy during HPV-associated carcinogenesis. Furthermore, noncoding RNA (ncRNA) expression profiling in cervical cancer has allowed the identification of autophagy-related ncRNAs associated with HPV. Autophagy-related genes are essential drivers of autophagy and are regulated by ncRNAs. We review the existing evidence regarding the role of autophagy-related proteins, the function of HPV E5, E6, and E7 oncoproteins, and the effects of noncoding RNA on autophagy regulation in the setting of cervical carcinogenesis. By characterizing the mechanisms behind the dysregulation of these critical factors and their impact on host cell autophagy, we advance understanding of the relationship between autophagy and progression from HPV infection to cervical cancer, and highlight pathways that can be targeted in preventive and therapeutic strategies against cervical cancer. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is the leading cause of death worldwide. Current data suggest that patients with cardiovascular diseases experience more serious complications with coronavirus disease-19 (COVID-19) than those without CVD. In addition, severe COVID-19 appears to cause acute cardiac injury, as well as long-term adverse remodeling of heart tissue. Cardiac fibroblasts and myofibroblasts, being crucial in response to injury, may play a pivotal role in both contributing to and healing COVID-19-induced cardiac injury. The role of cardiac myofibroblasts in cardiac fibrosis has been well-established in the literature for decades. However, with the emergence of the novel coronavirus SARS-CoV-2, new cardiac complications are arising. Bursts of inflammatory cytokines and upregulation of TGF-β1 and angiotensin (AngII) are common in severe COVID-19 patients. Cytokines, TGF-β1, and Ang II can induce cardiac fibroblast differentiation, potentially leading to fibrosis. This review details the key information concerning the role of cardiac myofibroblasts in CVD and COVID-19 complications. Additionally, new factors including controlling ACE2 expression and microRNA regulation are explored as promising treatments for both COVID-19 and CVD. Further understanding of this topic may provide insight into the long-term cardiac manifestations of the COVID-19 pandemic and ways to mitigate its negative effects. [ABSTRACT FROM AUTHOR]

T-cell intracellular antigen 1 (TIA1) is an RNA-binding protein that is primarily involved in the post-transcriptional regulation of cellular RNAs. Furthermore, it is a key component of stress granules (SGs), RNA, and protein aggregates that are formed in response to stressful stimuli to reduce cellular activity as a survival mechanism. TIA1 p.E384K mutation is the genetic cause of Welander distal myopathy (WDM), a late-onset muscular dystrophy whose pathogenesis has been related to modifying SG dynamics. In this study, we present the results obtained by analyzing two specific aspects: (i) SGs properties and dynamics depending on the amino acid at position 384 of TIA1; and (ii) the formation/disassembly time-course of TIA1WT/WDM-dependent SGs under oxidative stress. The generation of TIA1 variants—in which the amino acid mutated in WDM and the adjacent ones were replaced by lysines, glutamic acids, or alanines—allowed us to verify that the inclusion of a single lysine is necessary and sufficient to alter SGs dynamics. Moreover, time-lapse microscopy analysis allowed us to establish in vivo the dynamics of TIA1WT/WDM-dependent SG formation and disassembly, after the elimination of the oxidizing agent, for 1 and 3 h, respectively. Our observations show distinct dynamics between the formation and disassembly of TIA1WT/WDM-dependent SGs. Taken together, this study has allowed us to expand the existing knowledge on the role of TIA1 and the WDM mutation in SG formation. [ABSTRACT FROM AUTHOR]

Mounting data show that MIR139 is commonly silenced in solid cancer and hematological malignancies. MIR139 acts as a critical tumor suppressor by tuning the cellular response to different types of stress, including DNA damage, and by repressing oncogenic signaling pathways. Recently, novel insights into the mechanism of MIR139 silencing in tumor cells have been described. These include epigenetic silencing, inhibition of POL-II transcriptional activity on gene regulatory elements, enhanced expression of competing RNAs and post-transcriptional regulation by the microprocessor complex. Some of these MIR139-silencing mechanisms have been demonstrated in different types of cancer, suggesting that these are more general oncogenic events. Reactivation of MIR139 expression in tumor cells causes inhibition of tumor cell expansion and induction of cell death by the repression of oncogenic mRNA targets. In this review, we discuss the different aspects of MIR139 as a tumor suppressor gene and give an overview on different transcriptional mechanisms regulating MIR139 in oncogenic stress and across different types of cancer. The novel insights into the expression regulation and the tumor-suppressing activities of MIR139 may pave the way to new treatment options for cancer. [ABSTRACT FROM AUTHOR]

Williams syndrome (WS) is a multisystem neurodevelopmental disorder caused by a de novo hemizygous deletion of ~26 genes from chromosome 7q11.23, among them the general transcription factor II-I (GTF2I). By studying a novel murine model for the hypersociability phenotype associated with WS, we previously revealed surprising aberrations in myelination and cell differentiation properties in the cortices of mutant mice compared to controls. These mutant mice had selective deletion of Gtf2i in the excitatory neurons of the forebrain. Here, we applied diffusion magnetic resonance imaging and fiber tracking, which showed a reduction in the number of streamlines in limbic outputs such as the fimbria/fornix fibers and the stria terminalis, as well as the corpus callosum of these mutant mice compared to controls. Furthermore, we utilized next-generation sequencing (NGS) analysis of cortical small RNAs' expression (RNA-Seq) levels to identify altered expression of microRNAs (miRNAs), including two from the miR-34 cluster, known to be involved in prominent processes in the developing nervous system. Luciferase reporter assay confirmed the direct binding of miR-34c-5p to the 3'UTR of PTPRU—a gene involved in neural development that was elevated in the cortices of mutant mice relative to controls. Moreover, we found an age-dependent variation in the expression levels of doublecortin (Dcx)—a verified miR-34 target. Thus, we demonstrate the substantial effect a single gene deletion can exert on miRNA regulation and brain structure, and advance our understanding and, hopefully, treatment of WS. [ABSTRACT FROM AUTHOR]

Protein binding to the non-coding regions of mRNAs is relatively well characterized and its functionality has been described in many examples. New results obtained by high-throughput methods indicate that binding to the coding sequence (CDS) by RNA-binding proteins is also quite common, but the functions thereof are more obscure. As described in this review, CDS binding has a role in the regulation of mRNA stability, but it has also a more intriguing role in the regulation of translational efficiency. Global approaches, which suggest the significance of CDS binding along with specific examples of CDS-binding RBPs and their modes of action, are outlined here, pointing to the existence of a relatively less-known regulatory network controlling mRNA stability and translation on yet another level. [ABSTRACT FROM AUTHOR]