Search Results (138)

Heart failure with preserved ejection fraction (HFpEF) represents a growing global public health challenge, now accounting for approximately half of all heart failure cases and often linked to a systemic pathophysiological process in older adults with multiple comorbidities. Despite increasing recognition of the vascular contributions to HFpEF, the precise molecular mechanisms, particularly the role of noncoding Ribonucleic Acids (ncRNAs) in mediating vascular aging and subsequent cardiac dysfunction, remain incompletely understood. This review provides a comprehensive overview of the mechanistic link between vascular aging and HFpEF, with a specific focus on the pivotal roles of ncRNAs in this complex interplay. We delineate the classification of vascular aging, its cellular hallmarks, including endothelial senescence, vascular smooth muscle cell phenotypic switching, and extracellular matrix remodeling, and its systemic implications, such as inflammaging, oxidative stress, and reduced nitric oxide bioavailability. We then detail how these vascular alterations, including increased ventricular afterload and impaired myocardial perfusion due to coronary microvascular dysfunction, contribute to HFpEF pathophysiology. The review extensively discusses recent findings on how diverse classes of ncRNAs, notably microRNAs, long noncoding RNAs, and circular RNAs, along with emerging evidence for PIWI-interacting RNAs, small nuclear RNAs, small nucleolar RNAs, and tRNA-derived small RNAs, regulate these vascular aging processes and serve as molecular bridges connecting vascular dysfunction to heart failure. In conclusion, understanding the regulatory landscape of ncRNAs in vascular aging may reveal novel biomarkers and therapeutic avenues, offering new strategies for precision medicine in HFpEF. Full article

Background: Neurodevelopmental disorders, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), are increasingly recognized as conditions arising from multifaceted interactions among genetic predisposition, environmental exposures, and epigenetic modifications. Among epigenetic mechanisms, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and PIWI-interacting RNAs (piRNAs), have gained attention as pivotal regulators of gene expression during neurodevelopment. These RNA species do not encode proteins but modulate gene expression at transcriptional and post-transcriptional levels, thereby influencing neuronal differentiation, synaptogenesis, and plasticity. Objectives: This systematic review critically examines and synthesizes the most recent findings, particularly in the post-COVID transcriptomic research era, regarding the role of ncRNAs in the pathogenesis, diagnosis, and potential treatment of neurodevelopmental disorders. Methods: A comprehensive literature search was conducted to identify studies reporting on the expression profiles, functional implications, and clinical relevance of ncRNAs in neurodevelopmental disorders, across both human and animal models. Results: Here, we highlight that multiple classes of ncRNAs are differentially expressed in individuals with ASD and ADHD. Notably, specific miRNAs and lncRNAs demonstrate potential as diagnostic biomarkers with high sensitivity and specificity. Functional studies further reveal that ncRNAs actively contribute to pathogenic mechanisms by modulating neuronal gene networks. Conclusions: Emerging experimental data indicate that the exogenous administration of certain ncRNAs may reverse molecular and behavioral phenotypes, supporting their therapeutic promise. These findings broaden our understanding of neurodevelopmental regulation and open new avenues for personalized diagnostics and targeted interventions in clinical neuropsychiatry. Full article

Protein functional effector (pfe)RNAs were introduced in 2015 as PIWI-interacting-like small noncoding (nc)RNAs and were later categorized as a novel group based on being 2′-O-methylated at their 3′-end, directly binding and affecting protein function, but not levels, and not matching known RNAs. Here, we document that human pfeRNAs match fragments of GenBank database-annotated human ncRNAs. PDLpfeRNAa matches the 3′-half fragment of a mitochondrial transfer (t)RNA, and PDLpfeRNAb matches a 28S ribosomal (r)RNA fragment. These PDLpfeRNAs are known to bind to tumor programmed death ligand (PD-L)1, enhancing or inhibiting its interaction with lymphocyte PD-1 and consequently tumor immune escape, respectively. In a validated 8-pfeRNA-set classifier for pulmonary nodule presence and benign vs. malignant nature, seven here match one or more of the following: transfer, micro, Y, PIWI, long (lnc)RNAs, and a PDLpfeRNAa fragment. The previously identified chromosomal locations of these pfeRNAs and their matches partially overlap. Another 2-pfeRNA set was previously determined to distinguish between controls, patients with pulmonary tuberculosis, and those with lung cancer. One pfeRNA, previously shown to bind p60-DMAD and affect apoptosis, complements small nucleolar RNA SNORD45C, matching smaller 18S rRNA and lncRNA segments. Thus, pfeRNAs appear to have a common origin with known multifunctional ncRNA fragments. Differential modification may contribute to the multifunctionality of ncRNAs. For instance, for tRNA fragments, stabilizing 3′-end 2′-O-methylation, 3′-aminoacylation, and glycosylation modifications may regulate protein function, translation, and extracellular effects, respectively. One ncRNA gene can encode multiple fragments, multiple genes can encode the same fragment, and differentially modified ncRNA fragments might synergize or antagonize each other. Full article

The selective regulation of gene expression at the RNA level represents a rapidly evolving field offering substantial clinical potential. This review examines the molecular mechanisms of intracellular enzymatic systems that utilize single-stranded nucleic acids to downregulate specific RNA targets. The analysis encompasses antisense oligonucleotides and synthetic mimics of small interfering RNA (siRNA), microRNA (miRNA), transfer RNA-derived small RNA (tsRNA), and PIWI-interacting RNA (piRNA), elucidating their intricate interactions with crucial cellular machinery, specifically RNase H1, RNase P, AGO, and PIWI proteins, mediating their biological effects. The functional and structural characteristics of these endonucleases are examined in relation to their mechanisms of action and resultant therapeutic outcomes. This comprehensive analysis illuminates the interactions between single-stranded nucleic acids and their endonuclease partners, covering antisense inhibition pathways as well as RNA interference processes. This field of research has important implications for advancing targeted RNA modulation strategies across various disease contexts. Full article

Epigenetics and genome science have become central to current molecular biology research. Among the key mechanisms ensuring genomic integrity is the silencing of transposable elements in germline cells, a process essential for fertility in both sexes. A pivotal component of this silencing machinery involves PIWI-interacting RNAs (piRNAs), a distinct class of small non-coding RNAs that regulate gene expression and suppress transposable elements at both the transcriptional and post-transcriptional levels. piRNAs function in concert with PIWI proteins, whose expression is critical for proper oogenesis, spermatogenesis, and early zygote development. Disruptions in piRNA or PIWI protein pathways not only impair germline function but also contribute to genome instability, unchecked cell proliferation, and aberrant epigenetic modifications, hallmarks of tumorigenesis. Emerging evidence links the dysregulation of the piRNA/PIWI axis to the development and progression of various cancers, including lung and colorectal carcinomas. This review highlights the fundamental roles of piRNAs and PIWI proteins in reproductive biology and their increasingly recognized relevance in cancer biology. Full article

PiRNAs are a subclass of non-coding RNAs, 26–31 nucleotides (nt) in length, that form regulatory complexes through their interaction with PIWI proteins. Studies in model organisms have demonstrated that piRNAs play crucial roles in tissue development and in predicting disease outcomes, positioning them as promising targets for developmental regulation and therapeutic intervention. In contrast, research on piRNAs in animal husbandry is still in its early stages and has not received sufficient attention. Despite this, the few studies available in livestock research have revealed that piRNAs serve as key regulators of reproductive development, underscoring their significant regulatory potential in farm animals and justifying further investigation. Accordingly, this review uses the bovine mammary gland as an exemplary case to summarize the progress in piRNA research related to mammary development and disease. The role of piRNAs in regulating breast cancer stem cell proliferation and modulating inflammatory progression is a highly active area of research. We hypothesize that piRNAs may play a potential role in regulating both mammary gland development and mastitis, making them promising targets for enhancing mammary development and overall health in dairy cattle and providing a theoretical foundation for further piRNA applications in animal husbandry. Full article

Background: Physical activity induces a range of physiological and molecular adaptations, particularly affecting skeletal muscle and the cardiovascular system, regulating both tissue architecture and metabolic pathways. Emerging evidence suggests that PIWI-interacting RNAs (piRNAs) may serve as potential biomarkers for these adaptations. Here, we analyzed piRNA patterns in the context of exercise. Methods: This study selected eight participants of the iReAct study (DRKS00017446) for piRNA analysis. Baseline assessments included demographic profiling and fitness evaluation, particularly maximal oxygen uptake (V̇O2max) assessment. In addition, blood samples were collected pre- and (for six of the eight participants) post- standard reference training sessions. Subsequently, subjects underwent 6-week training protocols, employing standardized high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) regimens. Next, RNA sequencing was conducted to identify differentially expressed piRNAs, and correlation analyses were performed between piRNA expression patterns and training-associated changes in V̇O2max. Finally, to identify piRNAs potentially of interest in the context of exercise, different screening procedures were applied. Results: There were unique and specific changes in individual piRNA expression levels in response to exercise. In addition, we could define correlations of piRNA expression patterns, namely of piR-32886, piR-33151, piR-12547, and piR-33074, with changes in V̇O2max. These correlations did not reach significance in the small sample size of this pilot study, but might be verified in larger, confirming studies. Conclusions: This hypothesis-generating study identifies characteristic piRNA patterns in the context of exercise. Their significance as biomarkers is yet to be determined. Full article

Alzheimer’s disease (AD) is a leading cause of dementia worldwide. As current diagnostic approaches remain limited in sensitivity and accessibility, there is a critical need for novel, non-invasive biomarkers aiding early detection. Non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), PIWI-interacting RNAs (piRNAs), and small nucleolar RNAs (snoRNAs), have emerged as promising candidates due to their regulatory roles in gene expression and association with diseases. In this study, we systematically profiled ncRNA expression from RNA sequencing data of 48 AD and 22 control blood tissue samples, aiming to evaluate their utility as biomarkers for AD classification. Differential expression analysis revealed widespread dysregulation of lncRNAs and piRNAs, with over 5000 lncRNAs and nearly 1000 piRNAs significantly upregulated in AD. Weighted gene co-expression network analysis (WGCNA) identified multiple ncRNA modules associated with the AD phenotype. Using supervised machine learning approaches, we evaluated the diagnostic potential of ncRNA expression profiles, including single-gene, multi-gene, and module-level models. Random Forest models trained on individual genes identified 121 ncRNAs with AUROC > 0.8. Feature importance analysis emphasized ncRNAs such as lnc-MYEF2-3, lnc-PRKACB2, and HBII-115 as major contributors to diagnostic accuracy. These findings support the potential of ncRNA signatures as reliable and non-invasive biomarkers for AD diagnosis. Full article

Respiratory syncytial virus (RSV) is the leading cause of respiratory infections in children. Extracellular vesicles (EVs), released by airway epithelial cells, contain proteins and different families of non-coding RNAs (EV cargo) that can modulate the responses of target cells to viral infection. Nasal mucosa is a primary site of viral entry and the source of EVs present in the upper airway secretions. In this study we characterized proteins, including inflammatory mediators and cytokines, and the piwi-interacting RNA (piRNAs) cargo of EVs isolated from pediatric human nose organoids (HNO) and nasopharyngeal secretions (NPS) positive for RSV. Using Proximity Extension Assay (PEA) and Luminex multi-target arrays, we found significant enrichment in several chemokines and other mediators/biomarkers, including CCL2, CCL20, CXCL5, CX3CL1, CXCL6, MMP-1, MMP-10, uPA, Flt3L, ARNT and CD40 in EVs secreted by RSV-infected HNO compared to control mock HNO. Analysis of NPS samples from RSV infected children revealed that CCL3, CCL20, CXCL8, uPA, VEGFA, were concentrated in the NPS-EV fraction. LC-MS/MS and Gene Ontology indicated that RSV positive NPS-EVs originate from different cellular sources, with the most abundant proteins from neutrophils and epithelial cells. A total of 490 piRNAs were detected by NGS sequencing of small RNA libraries obtained from NPS-EVs, which has not been reported prior to this study. Identification of inflammatory mediators and small non-coding RNAs which are compartmentalized in EVs contributes to understanding mechanisms of virus-mediated pathogenesis in RSV infections. Full article

Follicular atresia is a natural process of follicular degeneration in mammal ovaries, significantly impacting female reproductive potential. However, the underlying regulatory mechanisms remain underexplored, particularly those involving non-coding RNAs like PIWI-interacting RNAs (piRNAs). In this study, we collected single antral follicles from the ovaries of 180-day-old commercial sows, classified them as healthy (HF) and atretic (AF) based on morphological and biochemical criteria, and sequenced the RNA samples using the Illumina Hiseq 3000 system (San Diego, CA, USA). piRNAs were identified using three algorithms, and the differential expression was compared and validated by qPCR. The target genes of differentially expressed piRNAs were predicted and subjected to functional analysis. A total of 452 piRNAs were identified across all samples, with 103 showing differential expression between HFs and AFs. Among the top 12 piRNAs with the most significant expression differences validated by qPCR, 5 (piR-23, piR-27, piR-64, piR-65, and piR-76) exhibited statistically significant differences. Pathway analysis showed that these piRNAs primarily targeted genes involved in cell apoptosis regulation, inflammation and oxidative stress response, substance transport and signal transduction, and cellular structural integrity maintenance. Our study provides the first comprehensive profile of piRNAs in porcine ovarian follicles during atresia and reveals underlying potential regulatory mechanisms. These findings enhance our understanding of piRNA functions during the early follicular atresia process and offer insights for further functional studies and biomarker development in ovarian pathology. Full article

Piwi-interacting RNAs (piRNAs) play a crucial role in silencing transposable elements (TEs) in the germ cells of Metazoa by acting as sequence-specific guides. Originating from distinct genomic loci, called piRNA clusters, piRNA can trigger an epigenetic conversion of TE insertions into piRNA clusters by means of a paramutation-like process. However, the variability in piRNA clusters’ capacity to induce such conversions remains poorly understood. Here, we investigated two Drosophila virilis strains with differing capacities to produce piRNAs from the subtelomeric RhoGEF3 and Adar gene loci. We found that active piRNA generation correlates with high levels of the heterochromatic mark histone 3 lysine 9 trimethylation (H3K9me3) over genomic regions that give rise to piRNAs. Importantly, the maternal transmission of piRNAs drives their production in the progeny, even from homologous loci previously inactive in piRNA biogenesis. The RhoGEF3 locus, once epigenetically converted, maintained enhanced piRNA production in subsequent generations lacking the original allele carrying the active piRNA cluster. In contrast, piRNA expression from the converted Adar locus was lost in offspring lacking the inducer allele. The present findings suggest that the paramutation-like behavior of piRNA clusters may be influenced not only by piRNAs but also by structural features and the chromatin environment in the proximity to telomeres, providing new insights into the epigenetic regulation of the Drosophila genome. Full article

Despite significant advancements in early detection and treatment, non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. Specifically, in early-stage cases, recurrence after surgery continues to be the principal cause of death for these patients. The urgent need for novel diagnostic and prognostic biomarkers has directed attention towards PIWI-interacting RNAs (piRNAs), a group of small RNAs that regulate genomic stability and epigenetics. Some piRNAs, including hsa_piR_022710, hsa_piR_019822, and hsa_piR_020840, have been described as deregulated in various cancers. This study investigated the expression of these three piRNAs by RT-qPCR in 277 NSCLC patients and developed survival and CART classification models to predict recurrence risk, overall survival (OS), and disease-free survival (DFS). hsa_piR_019822 and hsa_piR_020840 were able to discriminate between tumor and normal tissue, as well as between adenocarcinoma and squamous cell carcinoma (LUSC) patients. Elevated expression of hsa_piR_019822 and hsa_piR_022710 was correlated with an increased risk of recurrence and poorer DFS and OS in LUSC patients. Patients with high hsa_piR_022710 expression more greatly benefited from adjuvant treatment. In summary, higher piRNA levels were associated with an increased risk of recurrence and poorer survival outcomes, especially in LUSC patients, where they may help guide personalized treatment strategies. Full article

The cultivation of jujube (Ziziphus jujuba) in China is threatened by jujube witches’ broom (JWB) disease, a devastating infectious disease associated with JWB phytoplasma (‘Candidatus Phytoplasma ziziphi’). In many plants, proteins in the Argonaute (AGO) family, as main components of the RNA-induced silencing complex (RISC), play important roles in RNA silencing and pathogen resistance. The jujube telomere-to-telomere genome was searched by BLAST using Arabidopsis AGOs as probes. A total of nine jujube AGO gene members were identified, with each containing the conserved N-terminal, PZA, and PIWI domains. Phylogenetic analysis revealed that the nine jujube AGOs scattered into all three Arabidopsis AGO clades. Expression patterns of the ZjAGO genes were analyzed in response to phytoplasma in transcriptome data and by qRT–PCR. The jujube–phytoplasma interaction altered the expression of jujube AGO genes. ZjAGO1 and ZjAGO8 were up-regulated in the majority of the eight sampling periods subjected to qRT–PCR analysis. In the transcriptome data, ZjAGO1 and ZjAGO8 were also up-regulated during the key stages 37 and 39 weeks after grafting (WAG) with phytoplasma-infected material. These two jujube Argonaute genes may play important roles in response to JWB phytoplasma infection. Full article

Piwi-interacting RNAs (piRNAs) play an essential part in transposon suppression, DNA methylation, and antiviral responses. The current understanding of the roles of piRNAs in honeybees is very limited. This study aims to analyze the expression pattern and regulatory role of piRNAs in the Asian honeybee (Apis cerana) responding to infection by Nosema ceranae, based on previously gained small RNA-seq data. Here, 450 and 422 piRNAs were respectively identified in the midgut tissues of Apis cerana cerana workers at 7 and 10 days post-inoculation (dpi) with N. ceranae, including 539 non-redundant ones. Additionally, one up-regulated (piR-ace-1216942) and one down-regulated (piR-ace-776728) piRNA were detected in the workers’ midgut at 7 dpi, targeting 381 mRNAs involved in 31 GO terms, such as metabolic processes, catalytic activity, and organelles, as well as 178 KEGG pathways, including lysosome, MAPK signaling pathway, and purine metabolism. A total of 35 up-regulated and 11 down-regulated piRNAs were screened from the workers’ midgut at 10 dpi, targeting 13,511 mRNAs engaged in 50 GO terms, such as biological regulation, transporter activity, and membrane, as well as 389 KEGG pathways, including the JAK-STAT signaling pathway, Hippo signaling pathway, and nitrogen metabolism. Further analysis indicated that 28 differentially expressed piRNAs (DEpiRNAs) in the midgut at 10 dpi could target 299 mRNAs annotated to three cellular immune pathways (lysosome, endocytosis, and phagosome), while 24 DEpiRNAs could target 205 mRNAs relevant to four humoral immune pathways (FoxO, JAK-STAT, NF-κB, and MAPK signaling pathway). Through Sanger sequencing and RT-qPCR, the expression of six randomly selected DEpiRNAs was verified. Moreover, the dual-luciferase reporter gene assay confirmed the binding relationships between piR-ace-446232 and CRT as well as between piR-ace-1008436 and EGFR. Our findings not only contribute to enrich our understanding of the role of piRNAs in honeybees but also provide a basis for exploring the host response to N. ceranae infection mediated by piRNAs. Full article

PIWI-interacting RNAs (piRNAs) are small noncoding RNAs that are almost exclusively expressed in germ cells to silence harmful transposons to maintain genome stability. PIWIL4 is guided by its associated piRNAs to transposable elements, where it recruits the DNA methylation apparatus and instructs de novo DNA methylation. Herein, we identified a missense variant of PIWIL4 (c.805 C>T p.R269W) in two infertile males. Homozygous male mice carrying the orthologous knock-in variant displayed elevated transposable element expression and aberrant gene expression during the first wave of spermatogenesis, despite exhibiting normal sperm counts and morphology. Mechanistically, the mutated site altered the piRNA-binding ability of PIWIL4 and led to the derepression of endogenous LINE-1 elements. In summary, we identified a piRNA binding mutation in PIWIL4 that may be involved in human nonobstructive azoospermia. Full article