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Small extracellular vesicles (EVs) are released by cells and deliver biologically active payloads to coordinate the response of multiple cell types in cutaneous wound healing. Here we used a cutaneous injury model as a donor of pro-reparative EVs to treat recipient diabetic obese mice, a model of impaired wound healing. We established a functional screen for microRNAs (miRNAs) that increased the pro-reparative activity of EVs and identified a down-regulation of miR-425-5p in EVs in vivo and in vitro associated with the regulation of adiponectin. We tested a cell type-specific reporter of a tetraspanin CD9 fusion with GFP to lineage map the release of EVs from macrophages in the wound bed, based on the expression of miR-425-5p in macrophage-derived EVs and the abundance of macrophages in EV donor sites. Analysis of different promoters demonstrated that EV release under the control of a macrophage-specific promoter was most abundant and that these EVs were internalized by dermal fibroblasts. These findings suggested that pro-reparative EVs deliver miRNAs, such as miR-425-5p, that stimulate the expression of adiponectin that has insulin-sensitizing properties. We propose that EVs promote intercellular signaling between cell layers in the skin to resolve inflammation, induce proliferation of basal keratinocytes, and accelerate wound closure.

Genitourinary (GU) malignancies, including prostate, urothelial, kidney, testicular, penile, and adrenocortical cancers, comprise a significant burden of cancers worldwide. While many practice-changing advances have been made in the management of GU malignancies in the last decade, there is still significant room for improvement. MicroRNAs (miRNAs) are noncoding RNAs that regulate post-transcription gene expression and which have been implicated in multiple mechanisms of carcinogenesis. Therefore, they have the potential to revolutionize personalized cancer therapy, with several ongoing preclinical and clinical studies underway to investigate their efficacy. In this review, we describe the current landscape of miRNAs as diagnostics, therapeutics, and biomarkers of response for GU malignancies, reflecting a novel frontier in cancer treatment.

In a prospective cohort of subjects who subsequently developed preeclampsia (PE, n = 14) versus remaining healthy (NORM, n = 12), early gestation circulating extracellular vesicles (EVs) containing a panel of microRNA signatures were characterized and their biological networks of targets deciphered. Multiple microRNAs of which some arose from the placenta (19MC and 14MC) demonstrated changes in association with advancing gestation, while others expressed were pathognomonic of the subsequent development of characteristic clinical features of PE which set in as a late-onset subtype. This panel of miRNAs demonstrated a predictability with an area under the curve of 0.96 using leave-one-out cross-validation training in a logistic regression model with elastic-net regularization and precautions against overfitting. In addition, this panel of miRNAs, some of which were previously detected in either placental tissue or as maternal cell-free non-coding transcripts, lent further validation to our EV studies and the observed association with PE. Further, the identified biological networks of targets of these detected miRNAs revealed biological functions related to vascular remodeling, cellular proliferation, growth, VEGF, EGF and the PIP3/Akt signaling pathways, all mediating key cellular functions. We conclude that we have demonstrated a proof-of-principle by detecting a panel of EV packaged miRNAs in the maternal circulation early in gestation with possibilities of biological function in the placenta and other maternal tissues, along with the probability of predicting the subsequent clinical appearance of PE, particularly the late-onset subtype.

BACKGROUND/AIMS: While DNA methylation and gastric microbiome are each associated with gastric cancer (GC), their combined role in predicting GC remains unclear. This study investigated the potential of a combined DNA methylation and gastric microbiome signature to predict Helicobacter pylori-negative GC. METHODS: In this case-control study, we conducted quantitative methylation-specific polymerase chain reaction to measure the methylation levels of DKK3, SFRP1, EMX1, NKX6-1, MIR124-3, and TWIST1 in the gastric mucosa from 75 H. pylori-negative patients, including chronic gastritis (CG), intestinal metaplasia (IM), and GC. A combined analysis of DNA methylation and gastric microbiome, using 16S rRNA gene sequencing, was performed in 30 of 75 patients. RESULTS: The methylation levels of DKK3, SFRP1, EMX1, MIR124-3, and TWIST1 were significantly higher in patients with GC than in controls (all q

The clinical use of RNA interference (RNAi) molecular mechanisms has introduced a novel, growing class of RNA therapeutics capable of treating diseases by controlling target gene expression at the posttranscriptional level. With the newly approved nedosiran (Rivfloza), there are now six RNAi-based therapeutics approved by the United States Food and Drug Administration (FDA). Interestingly, five of the six FDA-approved small interfering RNA (siRNA) therapeutics [patisiran (Onpattro), lumasiran (Oxlumo), inclisiran (Leqvio), vutrisiran (Amvuttra), and nedosiran] were revealed to act on the 3'-untranslated regions of target mRNAs, instead of coding sequences, thereby following the common mechanistic action of genome-derived microRNAs (miRNA). Furthermore, three of the FDA-approved siRNA therapeutics [patisiran, givosiran (Givlaari), and nedosiran] induce target mRNA degradation or cleavage via near-complete rather than complete base-pair complementarity. These features along with previous findings confound the currently held characteristics to distinguish siRNAs and miRNAs or biosimilars, of which all converge in the RNAi regulatory pathway action. Herein, we discuss the RNAi mechanism of action and current criteria for distinguishing between miRNAs and siRNAs while summarizing the common and unique chemistry and molecular pharmacology of the six FDA-approved siRNA therapeutics. The term "RNAi" therapeutics, as used previously, provides a coherently unified nomenclature for broader RNAi forms as well as the growing number of therapeutic siRNAs and miRNAs or biosimilars that best aligns with current pharmacological nomenclature by mechanism of action. SIGNIFICANCE STATEMENT: The common and unique chemistry and molecular pharmacology of six FDA-approved siRNA therapeutics are summarized, in which nedosiran is newly approved. We point out rather a surprisingly mechanistic action as miRNAs for five siRNA therapeutics and discuss the differences and similarities between siRNAs and miRNAs that supports using a general and unified term "RNAi" therapeutics to align with current drug nomenclature criteria in pharmacology based on mechanism of action and embraces broader forms and growing number of novel RNAi therapeutics.

Synthetic biology constitutes a scientific domain focused on intentional redesign of organisms to confer novel functionalities or create new products through strategic engineering of their genetic makeup. Leveraging the inherent capabilities of nature, one may address challenges across diverse sectors including medicine. Inspired by this concept, we have developed an innovative bioengineering platform, enabling high-yield and large-scale production of biological small interfering RNA (BioRNA/siRNA) agents via bacterial fermentation. Herein, we show that with the use of a new tRNA fused pre-miRNA carrier, we can produce various forms of BioRNA/siRNA agents within living host cells. We report a high-level overexpression of nine target BioRNA/siRNA molecules at 100% success rate, yielding 3-10 mg of BioRNA/siRNA per 0.25 L of bacterial culture with high purity (>98%) and low endotoxin (

Because of their role in regulating and fine-tuning gene expression in the posttranscriptional period, microRNA (miRNA) may represent a mediating factor that connects diet and metabolic regulation. Given the vast number of miRNAs and that modulations in miRNA happen in response to a variety of stimuli, a comprehensive registry of miRNAs impacted by diet and the food items that modulate them, would have utility in the identification of miRNA complements for analysis of diet interventions and in helping to establish linkages between the specific impacts of diet components. A scoping literature search of online databases (PubMed, SCOPUS, EMBASE, and Web of Science) was performed. Only studies in human populations, those that used a diet intervention or meal challenge, and those that measured miRNA profiles in the same subject at multiple time points were included. Of the 6167 studies screened, only 25 met the study criteria and were included in the review. Seven studies examined miRNA following a meal challenge, whereas 18 investigated miRNA following a sustained diet intervention. The results demonstrated that miRNA are modulated following a variety of diet interventions and that intensity of miRNA response is greater in metabolically healthy subjects. Heterogeneity in the intensity and length of the diet intervention, the study populations being observed, and the methodology through which target miRNA are identified contribute to a lack of comparability across studies. The findings of this review highlight the need for more study of miRNA responsiveness to intake and provide recommendations for future research.

MicroRNAs (miRs) are short, evolutionarily conserved noncoding RNAs that canonically downregulate expression of target genes. The miR family composed of miR-204 and miR-211 is among the most highly expressed miRs in the retinal pigment epithelium (RPE) in both mouse and human and also retains high sequence identity. To assess the role of this miR family in the developed mouse eye, we generated two floxed conditional KO mouse lines crossed to the RPE65-ERT2-Cre driver mouse line to perform an RPE-specific conditional KO of this miR family in adult mice. After Cre-mediated deletion, we observed retinal structural changes by optical coherence tomography; dysfunction and loss of photoreceptors by retinal imaging; and retinal inflammation marked by subretinal infiltration of immune cells by imaging and immunostaining. Single-cell RNA sequencing of diseased RPE and retinas showed potential miR-regulated target genes, as well as changes in noncoding RNAs in the RPE, rod photoreceptors, and Müller glia. This work thus highlights the role of miR-204 and miR-211 in maintaining RPE function and how the loss of miRs in the RPE exerts effects on the neural retina, leading to inflammation and retinal degeneration.

Genome-derived microRNAs (miRNAs or miRs) govern posttranscriptional gene regulation and play important roles in various cellular processes and disease progression. While chemo-engineered miRNA mimics or biosimilars made in vitro are widely available and used, miRNA agents produced in vivo are emerging to closely recapitulate natural miRNA species for research. Our recent work has demonstrated the success of high-yield, in vivo production of recombinant miRNAs by using human tRNA (htRNA) fused precursor miRNA (pre-miR) carriers. In this study, we aim to compare the production of bioengineered RNA (BioRNA) molecules with glycyl versus leucyl htRNA fused hsa-pre-miR-34a carriers, namely, BioRNAGly and BioRNALeu, respectively, and perform the initial functional assessment. We designed, cloned, overexpressed, and purified a total of 48 new BioRNA/miRNAs, and overall expression levels, final yields, and purities were revealed to be comparable between BioRNAGly and BioRNALeu molecules. Meanwhile, the two versions of BioRNA/miRNAs showed similar activities to inhibit non-small cell lung cancer cell viability. Interestingly, functional analyses using model BioRNA/miR-7-5p demonstrated that BioRNAGly/miR-7-5p exhibited greater efficiency to regulate a known target gene expression (EGFR) than BioRNALeu/miR-7-5p, consistent with miR-7-5p levels released in cells. Moreover, BioRNAGly/miR-7-5p showed comparable or slightly greater activities to modulate MRP1 and VDAC1 expression, compared with miRCURY LNA miR-7-5p mimic. Computational modeling illustrated overall comparable 3D structures for exemplary BioRNA/miRNAs with noticeable differences in htRNA species and payload miRNAs. These findings support the utility of hybrid htRNA/hsa-pre-miR-34a as reliable carriers for RNA molecular bioengineering, and the resultant BioRNAs serve as functional biologic RNAs for research and development.

Acute lung injury (ALI) is characterized by respiratory failure resulting from the disruption of the epithelial and endothelial barriers as well as immune system. In this study, we evaluated the therapeutic potential of airway epithelial cell-derived extracellular vesicles (EVs) in maintaining lung homeostasis. We isolated human bronchial epithelial cell-derived EVs (HBEC-EVs), which endogenously express various immune-related surface markers and investigated their immunomodulatory potential in ALI. In ALI cellular models, HBEC-EVs demonstrated immunosuppressive effects by reducing the secretion of proinflammatory cytokines in both THP-1 macrophages and HBECs. Mechanistically, these effects were partially ascribed to nine of the top 10 miRNAs enriched in HBEC-EVs, governing toll-like receptor-NF-κB signaling pathways. Proteomic analysis revealed the presence of proteins in HBEC-EVs involved in WNT and NF-κB signaling pathways, pivotal in inflammation regulation. ANXA1, a constituent of HBEC-EVs, interacts with formyl peptide receptor (FPR)2, eliciting anti-inflammatory responses by suppressing NF-κB signaling in inflamed epithelium, including type II alveolar epithelial cells. In a mouse model of ALI, intratracheal administration of HBEC-EVs reduced lung injury, inflammatory cell infiltration, and cytokine levels. Collectively, these findings suggest the therapeutic potential of HBEC-EVs, through their miRNAs and ANXA1 cargo, in mitigating lung injury and inflammation in ALI patients.

The obesity epidemic continues to worsen worldwide, driving metabolic and chronic inflammatory diseases. Thiazolidinediones, such as rosiglitazone (Rosi), are PPARγ agonists that promote 'M2-like' adipose tissue macrophage (ATM) polarization and cause insulin sensitization. As ATM-derived small extracellular vesicles (ATM-sEVs) from lean mice are known to increase insulin sensitivity, we assessed the metabolic effects of ATM-sEVs from Rosi-treated obese male mice (Rosi-ATM-sEVs). Here we show that Rosi leads to improved glucose and insulin tolerance, transcriptional repolarization of ATMs and increased sEV secretion. Administration of Rosi-ATM-sEVs rescues obesity-induced glucose intolerance and insulin sensitivity in vivo without the known thiazolidinedione-induced adverse effects of weight gain or haemodilution. Rosi-ATM-sEVs directly increase insulin sensitivity in adipocytes, myotubes and primary mouse and human hepatocytes. Additionally, we demonstrate that the miRNAs within Rosi-ATM-sEVs, primarily miR-690, are responsible for these beneficial metabolic effects. Thus, using ATM-sEVs with specific miRNAs may provide a therapeutic path to induce insulin sensitization.

Extracellular vesicles (EVs) play important roles in cell-cell communication but are highly heterogeneous, and each vesicle has dimensions smaller than 200 nm with very limited amounts of cargos encapsulated. The technique of NanOstirBar (NOB)-EnabLed Single Particle Analysis (NOBEL-SPA) reported in the present work permits rapid inspection of single EV with high confidence by confocal fluorescence microscopy, thus enables colocalization assessment for selected protein and microRNA (miRNA) markers in the EVs produced by various cell lines, or present in clinical sera samples. EV subpopulations marked by the colocalization of unique protein and miRNA combinations were discovered to be able to detect early-stage (stage I or II) breast cancer (BC). NOBEL-SPA can be adapted to analyze other types of cargo molecules or other small submicron biological particles. Study of the sorting of specific cargos to heterogeneous vesicles under different physiological conditions can help discover distinct vesicle subpopulations valuable in clinical examination and therapeutics development and gain better understanding of their biogenesis.

The fetal brain of the mouse is thought to be dependent upon the placenta as a source of serotonin (5-hydroxytryptamine; 5-HT) and other factors. How factors reach the developing brain remains uncertain but are postulated here to be part of the cargo carried by placental extracellular vesicles (EV). We have analyzed the protein, catecholamine, and small RNA content of EV from mouse trophoblast stem cells (TSC) and TSC differentiated into parietal trophoblast giant cells (pTGC), potential primary purveyors of 5-HT. Current studies examined how exposure of mouse neural progenitor cells (NPC) to EV from either TSC or pTGC affect their transcriptome profiles. The EV from trophoblast cells contained relatively high amounts of 5-HT, as well as dopamine and norepinephrine, but there were no significant differences between EV derived from pTGC and from TSC. Content of miRNA and small nucleolar (sno)RNA, however, did differ according to EV source, and snoRNA were upregulated in EV from pTGC. The primary inferred targets of the microRNA (miRNA) from both pTGC and TSC were mRNA enriched in the fetal brain. NPC readily internalized EV, leading to changes in their transcriptome profiles. Transcripts regulated were mainly ones enriched in neural tissues. The transcripts in EV-treated NPC that demonstrated a likely complementarity with miRNA in EV were mainly up- rather than downregulated, with functions linked to neuronal processes. Our results are consistent with placenta-derived EV providing direct support for fetal brain development and being an integral part of the placenta-brain axis.

Testicular germ cell tumors (TGCTs) are relatively common in young men, making accurate diagnosis and prognosis assessment essential. MicroRNAs (miRNAs), including microRNA-371a-3p (miR-371a-3p), have shown promise as biomarkers for TGCTs. This review discusses the recent advancements in the use of miRNA biomarkers in TGCTs, with a focus on the challenges surrounding the noninvasive detection of teratomas. Circulating miR-371a-3p, which is expressed in undifferentiated TGCTs but not in teratomas, is a promising biomarker for TGCTs. Its detection in serum, plasma, and, potentially, cystic fluid could be useful for TGCT diagnosis, surveillance, and monitoring of therapeutic response. Other miRNAs, such as miR-375-3p and miR-375-5p, have been investigated to differentiate between TGCT subtypes (teratoma, necrosis/fibrosis, and viable tumors), which can aid in treatment decisions. However, a reliable marker for teratoma has yet to be identified. The clinical applications of miRNA biomarkers could spare patients from unnecessary surgeries and allow for more personalized therapeutic approaches. Particularly in patients with residual masses larger than 1 cm following chemotherapy, it is critical to differentiate between viable tumors, teratomas, and necrosis/fibrosis. Teratomas, which mimic somatic tissues, present a challenge in differentiation and require a comprehensive diagnostic approach. The combination of miR-371 and miR-375 shows potential in enhancing diagnostic precision, aiding in distinguishing between teratomas, viable tumors, and necrosis. The implementation of miRNA biomarkers in TGCT care could improve patient outcomes, reduce overtreatment, and facilitate personalized therapeutic strategies. However, a reliable marker for teratoma is still lacking. Future research should focus on the clinical validation and standardization of these biomarkers to fully realize their potential.

BACKGROUND: Diabetes is a spectrum of metabolic diseases affecting millions of people worldwide. The loss of pancreatic β-cell mass by either autoimmune destruction or apoptosis, in type 1-diabetes (T1D) and type 2-diabetes (T2D), respectively, represents a pathophysiological process leading to insulin deficiency. Therefore, therapeutic strategies focusing on restoring β-cell mass and β-cell insulin secretory capacity may impact disease management. This study took advantage of powerful integrative bioinformatic tools to scrutinize publicly available diabetes-associated gene expression data to unveil novel potential molecular targets associated with β-cell dysfunction. METHODS: A comprehensive literature search for human studies on gene expression alterations in the pancreas associated with T1D and T2D was performed. A total of 6 studies were selected for data extraction and for bioinformatic analysis. Pathway enrichment analyses of differentially expressed genes (DEGs) were conducted, together with protein-protein interaction networks and the identification of potential transcription factors (TFs). For noncoding differentially expressed RNAs, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which exert regulatory activities associated with diabetes, identifying target genes and pathways regulated by these RNAs is fundamental for establishing a robust regulatory network. RESULTS: Comparisons of DEGs among the 6 studies showed 59 genes in common among 4 or more studies. Besides alterations in mRNA, it was possible to identify differentially expressed miRNA and lncRNA. Among the top transcription factors (TFs), HIPK2, KLF5, STAT1 and STAT3 emerged as potential regulators of the altered gene expression. Integrated analysis of protein-coding genes, miRNAs, and lncRNAs pointed out several pathways involved in metabolism, cell signaling, the immune system, cell adhesion, and interactions. Interestingly, the GABAergic synapse pathway emerged as the only common pathway to all datasets. CONCLUSIONS: This study demonstrated the power of bioinformatics tools in scrutinizing publicly available gene expression data, thereby revealing potential therapeutic targets like the GABAergic synapse pathway, which holds promise in modulating α-cells transdifferentiation into β-cells.

microRNAs (miRNAs) have a broad influence on gene expression; however, we have limited insights into their contribution to rate of cognitive decline over time or Alzheimer's disease (AD). Given this, we tested associations of 528 miRNAs with cognitive trajectory, AD hallmark pathologies, and AD clinical diagnosis using small RNA sequencing from the dorsolateral prefrontal cortex of 641 community-based donors. We found 311 miRNAs differentially expressed in AD or its endophenotypes after adjusting for technical and sociodemographic variables. Among these, 137 miRNAs remained differentially expressed after additionally adjusting for several co-occurring age-related cerebral pathologies, suggesting that some miRNAs are associated with the traits through co-occurring pathologies while others through mechanisms independent from pathologies. Pathway enrichment analysis of downstream targets of these differentially expressed miRNAs found enrichment in transcription, postsynaptic signalling, cellular senescence, and lipoproteins. In sex-stratified analyses, five miRNAs showed sex-biased differential expression for one or more AD endophenotypes, highlighting the role that sex has in AD. Lastly, we used Mendelian randomization to test whether the identified differentially expressed miRNAs contribute to the cause or are the consequence of the traits. Remarkably, 15 differentially expressed miRNAs had evidence consistent with a causal role, laying the groundwork for future mechanistic studies of miRNAs in AD and its endophenotypes.

The Diabetes Prevention Program (DPP) randomized controlled trial demonstrated that metformin treatment reduced progression to type 2 diabetes (T2D) by 31% compared to placebo in adults with prediabetes. Circulating micro-ribonucleic acids (miRs) are promising biomarkers of T2D risk, but little is known about their associations with metformin regimens for T2D risk reduction. We compared the change in 24 circulating miRs from baseline to 2 years in a subset from DPP metformin intervention (n = 50) and placebo (n = 50) groups using Wilcoxon signed rank tests. Spearman correlations were used to evaluate associations between miR change and baseline clinical characteristics. Multiple linear regression was used to adjust for covariates. The sample was 73% female, 17% Black, 13% Hispanic, and 50 ± 11 years. Participants were obese, normotensive, prediabetic, and dyslipidemic. Change in 12 miR levels from baseline to 2 years was significantly different in the metformin group compared with placebo after adjusting for multiple comparisons: six (let-7c-5p, miR-151a-3p, miR-17-5p, miR-20b-5p, miR-29b-3p, and miR-93-5p) were significantly upregulated and six (miR-130b-3p, miR-22-3p, miR-222-3p, miR-320a-3p, miR-320c, miR-92a-3p) were significantly downregulated in the metformin group. These miRs help to explain how metformin is linked to T2D risk reduction, which may lead to novel biomarkers, therapeutics, and precision health strategies.

Breast cancer metastasis to the brain is a clinical challenge rising in prevalence. However, the underlying mechanisms, especially how cancer cells adapt a distant brain niche to facilitate colonization, remain poorly understood. A unique metabolic feature of the brain is the coupling between neurons and astrocytes through glutamate, glutamine, and lactate. Here we show that extracellular vesicles from breast cancer cells with a high potential to develop brain metastases carry high levels of miR-199b-5p, which shows higher levels in the blood of breast cancer patients with brain metastases comparing to those with metastatic cancer in other organs. miR-199b-5p targets solute carrier transporters (SLC1A2/EAAT2 in astrocytes and SLC38A2/SNAT2 and SLC16A7/MCT2 in neurons) to hijack the neuron-astrocyte metabolic coupling, leading to extracellular retention of these metabolites and promoting cancer cell growth. Our findings reveal a mechanism through which cancer cells of a non-brain origin reprogram neural metabolism to fuel brain metastases.

Recently, the siRNAs pathways, and especially reproductive phasiRNAs, have attracted attention in eudicots since their biological roles are still unknown and their biogenesis took different evolutionary pathways compared to monocots. In this work, we used Coffea arabica L., a recent allotetraploid formed from the hybridization of Coffea canephora and C. eugenioides unreduced gametes, to explore microsporogenesis and small RNAs-related pathways in a eudicot crop. First, we identified the microsporogenesis stages during anther development revealing that pre-meiosis occurs in anthers of 1.5 mm inside floral buds (FBs), whereas meiosis between 1.5 and 4.2 mm FBs, and post-meiosis in FBs larger than 4.2 mm. These stages coincide with the Brazilian winter, a period of FBs reduced growth which suggests temperature sensitivity. Next, we identified and quantified the expression of reproductive 21- and 24-nt phasiRNAs during coffee anther development together with their canonical and novel miRNA triggers, and characterized the DCL and AGO families. Our results showed that the pattern of reproductive phasiRNA abundance in C. arabica is unique among described eudicots and the canonical trigger car-miR2275 is involved in the processing of both 21- and 24-nt phasiRNAs. Fourteen DCL genes were identified, but DCL5, related to phasiRNA biosynthesis in monocots, was not, according to its specificity for monocots. Thus, our work explored the knowledge gap about microsporogenesis and related siRNAs pathways in coffee, contributing to the control of reproductive development and the improvement of fertility in eudicots.

Despite rapid evolution across eutherian mammals, the X-linked MIR-506 family miRNAs are located in a region flanked by two highly conserved protein-coding genes (SLITRK2 and FMR1) on the X chromosome. Intriguingly, these miRNAs are predominantly expressed in the testis, suggesting a potential role in spermatogenesis and male fertility. Here, we report that the X-linked MIR-506 family miRNAs were derived from the MER91C DNA transposons. Selective inactivation of individual miRNAs or clusters caused no discernible defects, but simultaneous ablation of five clusters containing 19 members of the MIR-506 family led to reduced male fertility in mice. Despite normal sperm counts, motility, and morphology, the KO sperm were less competitive than wild-type sperm when subjected to a polyandrous mating scheme. Transcriptomic and bioinformatic analyses revealed that these X-linked MIR-506 family miRNAs, in addition to targeting a set of conserved genes, have more targets that are critical for spermatogenesis and embryonic development during evolution. Our data suggest that the MIR-506 family miRNAs function to enhance sperm competitiveness and reproductive fitness of the male by finetuning gene expression during spermatogenesis.

Background: Glioblastoma remains a highly invasive primary brain malignancy with an undesirable prognosis. Growing evidence has shed light on the importance of microRNAs (miRs), as small non-coding RNAs, in tumor development and progression. The present study leverages the in-silico and in-vitro techniques to investigate the significance of hsa-miR-181a-5p and the underlying hsa-miR-181a-5p-meidated signaling pathway in glioblastoma development. Methods: Bioinformatic studies were performed on GSE158284, GSE108474 (REMBRANDT study), TCGA-GTEx, CCLE, GeneMANIA, Reactome, WikiPathways, KEGG, miRDB, and microT-CDS to identify the significance of hsa-miR-181a-5p and its underlying target. Afterward, the U373 cell line was selected and transfected with hsa-miR-181a-5p mimics, and the cell viability, clonogenicity, migration, mRNA expression, apoptosis, and cell cycle were studied using the MTT assay, colony formation test, migration assay, qRT-PCR, and flow cytometry respectively. Results: hsa-miR-181a-5p expression is decreased in glioblastoma samples. The in-silico results have shown that hsa-miR-181a-5p could regulate the MAPK pathway by targeting AKT3. The experimental assays have shown that hsa-miR-181a-5p decreases the migration of glioblastoma cells, arrests the cell cycle, and increases the apoptosis rate. Besides downregulating MMP9 and upregulating BAX, hsa-miR-181a-5p downregulates MET, MAP2K1, MAPK1, MAPK3, and AKT3 expression in U373 cells. The in-vitro results were consistent with in-silico results regarding the regulatory effect of hsa-miR-181a-5p on the MAPK pathway, leading to tumor suppression in glioblastoma. Conclusions: hsa-miR-181a-5p inhibits glioblastoma development partially by regulating the signaling factors of the MAPK pathway. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Methods Results Conclusion Intestinal ischemia‐reperfusion injury (IIRI) is common in a variety of critical diseases and acute stress, and acupuncture is a promising treatment for IIRI. The aim of this study is to explore the mechanism of electroacupuncture (EA) at Zusanli (ST36) in improving IIRI from the perspective of the cholinergic anti‐inflammatory pathway (CAP) and miRNA 124.Seven groups of mice were performed: Control group, I/R group (IIRI model), EA group (I/R + EA), miRNA mimic group (I/R + EA + miRNA 124 mimic), miRNA inhibitor group (I/R + EA + miRNA 124 inhibitor), PNU group (I/R + EA + α7nAChR agonist), and MLA group (I/R + EA+ α7nAChR antagonist). The expression of intestinal macrophages, α7nAChR, miRNA 124, and related molecules, including p‐STAT3 and IL‐6, as well as histological damage (Chiu's score) and mucosal permeability (serum FD4 concentration), were detected.The serum FD4 concentrations in the EA and PNU groups were significantly lower compared to the I/R group (p < 0.05). The expression of intestinal α7nAChR and miRNA 124 in the EA, miRNA mimic, and PNU groups was higher than that in the I/R group (p < 0.05), while levels of p‐STAT3 and IL‐6 were reduced (p < 0.05). Conversely, in the miRNA inhibitor and MLA groups, miRNA 124 levels were significantly lower than in the EA group (p < 0.05), and IL‐6 levels were increased (p < 0.05).EA at Zusanli may induce miRNA124 through the cholinergic pathway on intestinal macrophages, which may be a key neuro‐immune target of EA in the treatment of IIRI. [ABSTRACT FROM AUTHOR]

• Prostate cancer (PC) is a leading cause of cancer-related mortality in men. MicroRNAs (miRNAs) have emerged as major molecules involved in the progress of PC. • Dysregulated miRNAs are critical in PC progression. • Oncogenic miRNAs may lead to the advancement of new targeted cures for improved patient outcomes. Prostate cancer (PC) is a leading cause of cancer-related mortality in men worldwide, and identifying key molecular players in its pathogenesis is essential for advancing effective diagnosis and therapy. MicroRNAs (miRNAs) have recently emerged as significant molecules involved in the progression of various cancers. As noncoding RNAs, miRNAs play a vital role in regulating gene expression and are implicated in several aspects of cancer pathogenesis. In the context of human PC, growing evidence suggests that certain miRNAs with oncogenic properties are key players in the initiation, progression, and metastasis of the disease. In conclusion, dysregulated miRNAs are critical in prostate cancer progression, influencing key cellular processes. Oncogenic miRNAs exhibit diagnostic and therapeutic potential in PC. Targeting these miRNAs presents novel treatment avenues, but further research is needed to fully understand their clinical utility. Additional investigation into the mechanisms of miRNA regulation and their interactions with other signaling pathways is necessary to comprehensively understand the role of oncogenic miRNAs in PC and to develop effective treatments for this disease. Overall, substantiating the role of oncogenic miRNAs in PC pathogenesis provides valuable insights into the mechanisms underlying the disease and may lead to the development of novel targeted therapies for improved patient outcomes. [ABSTRACT FROM AUTHOR]

This study was to investigate the mechanism of Changma Xifeng tablet, a traditional Chinese medicine in the treatment of Tourette syndrome. Network pharmacology was utilized to pinpoint blood-entering constituents of Changma Xifeng and explore their potential targets. Additionally, differential microRNA expression analysis was conducted to predict Tourette syndrome-associated targets, complemented by molecular docking and dynamics simulations to support the interactions of the active compounds with these targets. The study identified 98 common targets between Changma Xifeng and Tourette syndrome, which may be involved in the treatment process. A protein-protein interaction network and a drug-active ingredient-disease target network highlighted the formulation's multi-component, multi-target therapeutic approach. Eight pivotal targets-AR, GRM5, MET, RORA, HTR2A, CNR1, PDE4B, and TOP1-were identified at the intersection of microRNA and drug targets. Molecular docking revealed 12 complexes with favorable binding energies below − 7 kcal/mol, specifically: AR with Alfacalcidol, TOP1 with Albiflorin, GRM5 with Arachidic Acid, GRM5 with Palmitic Acid, AR with Arachidic Acid, AR with 2-Hydroxyoctadecanoic Acid, RORA with Pinellic Acid, RORA with Palmitic Acid, AR with Acoronene, AR with Epiacoronene, AR with 4,4'-Methylenediphenol, and HTR2A with Calycosin. Our molecular docking and molecular dynamics simulations suggest potential stable interactions between the formulation's active components and target proteins. These computational methods provide a preliminary theoretical framework that will guide our future experimental work. The study provides a scientific rationale for the use of traditional Chinese medicine in Tourette syndrome management and offers new insights for drug development. [ABSTRACT FROM AUTHOR]

Sepsis-associated acute kidney injury (S-AKI) is a common disease in pediatric intensive care units (ICU) with high morbidity and mortality. The newly discovered results indicate that microRNAs (miRNAs) play an important role in the diagnosis and treatment of S-AKI and can be used as markers for early diagnosis. In this study, the expression level of miR-16-5p was found to be significantly upregulated about 20-fold in S-AKI patients, and it also increased by 1.9 times in the renal tissue of S-AKI mice. Receiver operating characteristic (ROC) curve analysis showed that miR-16-5p had the highest predictive accuracy in the diagnosis of S-AKI (AUC = 0.9188). In vitro, the expression level of miR-16-5p in HK-2 cells treated with 10 μg/mL lipopolysaccharide (LPS) increased by more than 2 times. In addition, LPS-exposed renal tissue and HK-2 cells lead to upregulation of inflammatory cytokines IL-6, IL-1β, TNF-a, and kidney damage molecules kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL). However, inhibition of miR-16-5p significantly mitigated LPS expose-mediated kidney injury and inflammation. Furthermore, LPS-exposed HK-2 cells increased more than 1.7-fold the expression levels of Bax and caspase-3, decreased 3.2-fold the expression level of B-cell lymphoma-2 (Bcl-2), and significantly promoted the occurrence of apoptosis. MiR-16-5p mimic further increased LPS-induced apoptosis in HK-2 cells. Nevertheless, inhibition of miR-16-5p significantly attenuated this effect. In summary, up-regulation of miR-16-5p expression can significantly aggravate renal injury and apoptosis in S-AKI, which also proves that miR-16-5p can be used as a potential biomarker to promote early identification of S-AKI. [ABSTRACT FROM AUTHOR]

BACKGROUND: Distinguishing between unilateral and bilateral primary aldosteronism, a major cause of secondary hypertension, is crucial due to different treatment approaches. While adrenal venous sampling is the gold standard, its invasiveness, limited availability, and often difficult interpretation pose challenges. This study explores the utility of circulating microRNAs (miRNAs) and machine learning in distinguishing between unilateral and bilateral forms of primary aldosteronism. METHODS: MiRNA profiling was conducted on plasma samples from 18 patients with primary aldosteronism taken during adrenal venous sampling on an Illumina MiSeq platform. Bioinformatics and machine learning identified 9 miRNAs for validation by reverse transcription real-time quantitative polymerase chain reaction. Validation was performed on a cohort consisting of 108 patients with known subdifferentiation. A 30-patient subset of the validation cohort involved both adrenal venous sampling and peripheral, the rest only peripheral samples. A neural network model was used for feature selection and comparison between adrenal venous sampling and peripheral samples, while a deep-learning model was used for classification. RESULTS: Our model identified 10 miRNA combinations achieving >85% accuracy in distinguishing unilateral primary aldosteronism and bilateral adrenal hyperplasia on a 30-sample subset, while also confirming the suitability of peripheral samples for analysis. The best model, involving 6 miRNAs, achieved an area under curve of 87.1%. Deep learning resulted in 100% accuracy on the subset and 90.9% sensitivity and 81.8% specificity on all 108 samples, with an area under curve of 86.7%. CONCLUSIONS: Machine learning analysis of circulating miRNAs offers a minimally invasive alternative for primary aldosteronism lateralization. Early identification of bilateral adrenal hyperplasia could expedite treatment initiation without the need for further localization, benefiting both patients and health care providers. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is an aggressive type IV brain tumor that originates from astrocytes and has a poor prognosis. Despite intensive research, survival rates have not significantly improved. Noncoding RNAs (ncRNAs) are emerging as critical regulators of carcinogenesis, progression, and increased treatment resistance in GBM cells. They influence angiogenesis, migration, epithelial-to-mesenchymal transition, and invasion in GBM cells. ncRNAs, such as long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are commonly dysregulated in GBM. miRNAs, such as miR-21, miR‐133a, and miR‐27a‐3p, are oncogenes that increase cell proliferation, metastasis, and migration by targeting TGFBR1 and BTG2. In contrast, lncRNAs, such as HOXD-AS2 and LINC00511, are oncogenes that increase the migration, invasion, and proliferation of cells. CircRNAs, such as circ0001730, circENTPD7, and circFOXO3, are oncogenes responsible for cell growth, angiogenesis, and viability. Developing novel therapeutic strategies targeting ncRNAs, cell migration, and angiogenesis is a promising approach for GBM. By targeting these dysregulated ncRNAs, we can potentially restore a healthy balance in gene expression and influence disease progression. ncRNAs abound within GBM, demonstrating significant roles in governing the growth and behavior of these tumors. They may also be useful as biomarkers or targets for therapy. The use of morpholino oligonucleotides (MOs) suppressing the oncogene expression of HOTAIR, BCYRN1, and cyrano, antisense oligonucleotides (ASOs) suppressing the expression of ncRNAs such as MALAT1 and miR-10b, locked nucleic acids (LNAs) suppressing miR-21, and peptide nucleic acids (PNAs) suppressing the expression of miR-155 inhibited the PI3K pathway, tumor growth, angiogenesis, proliferation, migration, and invasion. Targeting oncogenic ncRNAs with RNA-interfering strategies such as MOs, ASOs, LNAs, CRISPR-Cas9 gene editing, and PNA approaches may represent a promising therapeutic strategy for GBM. This review emphasizes the critical role of ncRNAs in GBM pathogenesis, as well as the potential for new therapeutic strategies targeting these pathways to improve the prognosis and quality of life for GBM patients. Noncoding RNAs in glioblastoma play a dual role as both tumor suppressors and oncogenes, intricately regulating gene expression and contributing to the complex molecular landscape of this aggressive brain cancer. [ABSTRACT FROM AUTHOR]

Inflammation and autoimmune diseases (AD) are common outcomes of an overactive immune system. Inflammation occurs due to the immune system reacting to damaging stimuli. Exosomes are being recognized as an advanced therapeutic approach for addressing an overactive immune system, positioning them as a promising option for treating AD. Mesenchymal stem cells (MSCs) release exosomes that have strong immunomodulatory effects, influenced by their cell of origin. MSCs-exosomes, being a cell-free therapy, exhibit less toxicity and provoke a diminished immune response compared to cell-based therapies. Exosomal non-coding RNAs (ncRNA), particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are intricately linked to various biological and functional aspects of human health. Exosomal ncRNAs can lead to tissue malfunction, aging, and illnesses when they experience tissue-specific alterations as a result of various internal or external problems. In this study, we will examine current trends in exosomal ncRNA researches regarding AD. Then, therapeutic uses of MSCs-exosomal ncRNA will be outlined, with a particle focus on the underlying molecular mechanisms. [ABSTRACT FROM AUTHOR]

A study in the British Journal of Pharmacology examined the relationship between plasma miR-1-3p levels and severity in hospitalized COVID-19 patients. The research revealed that elevated miR-1-3p levels were associated with severe cases of COVID-19, leading to longer hospital stays and higher mortality rates. Inhibiting miR-1-3p reversed the impaired angiogenic capacity caused by severe COVID-19 plasma, suggesting that miR-1-3p could be a valuable prognostic biomarker for predicting severity and survival in COVID-19 patients. The study also highlighted the impact of miRNAs on biological processes related to blood coagulation, platelet activation, and viral processes, emphasizing the role of endothelial cells and cardiomyocytes in COVID-19 pathophysiology. [Extracted from the article]

Spinal cord injury (SCI) is a debilitating condition characterized by significant sensory, motor, and autonomic dysfunctions, leading to severe physical, psychological, and financial burdens. The current therapeutic approaches for SCI show limited effectiveness, highlighting the urgent need for innovative treatments. MicroRNAs (miRNAs) like miR-10b-5p are known to play pivotal roles in gene expression regulation and have been implicated in various neurodegenerative diseases, including SCI. Polypyrimidine tract binding protein 1 (PTBP1) has also been associated with neural injury responses and recovery. This study aims to explore the interaction between miR-10b-5p and PTBP1 in the context of SCI, hypothesizing that miR-10b-5p regulates PTBP1 to influence SCI pathogenesis and recovery using a rat model of SCI and lipopolysaccharide (LPS)-induced PC12 cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to measure miR-10b-5p levels, revealing its low expression in SCI rats. We then assessed neurological function, histopathological changes, and spinal cord water content. We found that administering the agomiR-10b-5p significantly improved neurological function and decreased the spinal cord water content and normal motor neuron loss in SCI rats. Additionally, we explored the functions of miR-10b-5p in LPS-treated PC12 cells. Our results showed that miR-10b-5p repressed LPS-stimulated apoptosis, inflammation, and oxidative stress in PC12 cells. PTBP1 was predicted as a potential target gene of miR-10b-5p using the TargetScan database. Pulldown and luciferase reporter assays further demonstrated that miR-10b-5p binds to the 3' untranslated region (UTR) of PTBP1. RT-qPCR revealed that miR-10b-5p negatively modulated PTBP1 expression both in vivo and in vitro. Furthermore, rescue assays indicated that miR-10b-5p alleviated SCI in rats and LPS-triggered injury in PC12 cells by downregulating PTBP1. We also investigated the regulation of miR-10b-5p and PTBP1 on the transforming growth factor-beta 1 (TGF-β1)/small mother against decapentaplegic (Smad3) pathway. We found that miR-10b-5p targeted PTBP1 to repress TGF-β1 decay and facilitated TGF-β1/Smad3 pathway activation. In conclusion, our results demonstrate that miR-10b-5p alleviates SCI by repressing TGF-β1 decay and inducing TGF-β1/Smad3 pathway activation through PTBP1 downregulation. This study provides novel insights into potential targeted therapy plans for SCI. [ABSTRACT FROM AUTHOR]

The differentiation/maturation trajectories of different blood cell types stemming from a CD34+ common ancestor takes place in different biologically relevant multidimensional spaces. Here, we generated microRNA and cytokine profiles from highly purified populations of hematopoietic progenitors/precursors derived from cord blood hematopoietic stem/progenitor cells. MicroRNA and cytokine landscapes were then analyzed to find their mutual relationships under the hypothesis that the highly variable miRNome corresponds to the 'force field' driving the goal of a stable phenotype (here corresponding to the cytokine abundance pattern) typical of each cell kind. The high dimensionality and lack of linearity of the hematopoietic process pushed us to adopt a distance–geometry approach to compare different trajectories, while a complex network analysis was instrumental in revealing the fine structure of microRNA–cytokine relations. Importantly, the approach enabled us to identify a limited number of factors (represented either by microRNAs or cytokines) corresponding to crucial nodes responsible for connecting distinct interaction modules. Subtle changes in 'master nodes', keeping the connections between different regulatory networks, may therefore be crucial in influencing hematopoietic differentiation. These findings highlight the extremely interconnected network structures underlying hematopoiesis regulation and identify key factors in the microRNA/cytokine landscape that may be potentially crucial for influencing network stability. [ABSTRACT FROM AUTHOR]

RNA therapeutics have undergone remarkable evolution since their inception in the late 1970s, revolutionizing medicine by offering new possibilities for treating previously intractable diseases. The field encompasses various modalities, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs), each with unique mechanisms and applications. The foundation was laid in 1978 with the discovery that synthetic oligonucleotides could inhibit viral replication, followed by pivotal developments such as RNA interference's discovery in 1998. The COVID-19 pandemic marked a crucial turning point, demonstrating the potential of mRNA vaccines and accelerating interest in RNA-based approaches. However, significant challenges remain, including stability issues, delivery to target tissues, potential off-target effects, and immunogenicity concerns. Recent advancements in chemical modifications, delivery systems, and the integration of AI technologies are addressing these challenges. The field has seen notable successes, such as approved treatments for spinal muscular atrophy and hereditary transthyretin-mediated amyloidosis. Looking ahead, RNA therapeutics show promise for personalized medicine approaches, particularly in treating genetic disorders and cancer. The continued evolution of this field, driven by technological innovations and deeper understanding of RNA biology, suggests a transformative impact on future medical treatments. The purpose of this review is to provide a comprehensive overview of the evolution, current state, and prospects of RNA therapeutics. [ABSTRACT FROM AUTHOR]

Cardiotoxicity (CDTX) is a critical side effect of many cancer therapies, leading to increased morbidity and mortality if not addressed. Early detection of CDTX is essential, and while echocardiographic measures like global longitudinal strain offer promise in identifying early myocardial dysfunction, the search for reliable biomarkers continues. MicroRNAs (miRNAs) are emerging as important non-coding RNA molecules that regulate gene expression post-transcriptionally, influencing key biological processes such as the cell cycle, apoptosis, and stress responses. In cardiovascular diseases, miRNAs have demonstrated potential as biomarkers due to their stability in circulation and specific expression patterns that reflect pathological changes. Certain miRNAs have been linked to CDTX and hold promise for early detection, prognosis, and therapeutic targeting. These miRNAs not only assist in identifying early cardiac injury, but also offer opportunities for personalized interventions by modulating their expression to influence disease progression. As research advances, integrating miRNA profiling with traditional diagnostic methods could enhance the management of CDTX in cancer patients, paving the way for improved patient outcomes and more tailored therapeutic strategies. Further clinical studies are essential to validate the clinical utility of miRNAs in managing CDTX. [ABSTRACT FROM AUTHOR]

Breast cancer is a heterogeneous disease comprising multiple molecularly distinct subtypes with varied prevalence, prognostics, and treatment strategies. Among them, triple-negative breast cancer, though the least prevalent, is the most aggressive subtype, with limited therapeutic options. Recent emergence of competing endogenous RNA (ceRNA) networks has highlighted how long noncoding RNAs (lncRNAs), microRNAs (miRs), and mRNA orchestrate a complex interplay meticulously modulating mRNA functionality. Focusing on TNBC, this study aimed to construct a ceRNA network using differentially expressed lncRNAs, miRs, and mRNAs. We queried the differentially expressed lncRNAs (DElncRNAs) between TNBC and luminal samples and found 389 upregulated and 386 downregulated lncRNAs, including novel transcripts in TNBC. DElncRNAs were further evaluated for their clinical, functional, and mechanistic relevance to TNBCs using the lnc2cancer 3.0 database, which presented LUCAT1 (lung cancer-associated transcript 1) as a putative node. Next, the ceRNA network (lncRNA–miRNA–mRNA) of LUCAT1 was established. Several miRNA–mRNA connections of LUCAT1 implicated in regulating stemness (LUCAT1-miR-375-Yap1, LUCAT1-miR181-5p-Wnt, LUCAT1-miR-199a-5p-ZEB1), apoptosis (LUCAT1-miR-181c-5p-Bcl2), drug efflux (LUCAT1-miR-200c-ABCB1, LRP1, MRP5, MDR1), and sheddase activities (LUCAT1-miR-493-5p-ADAM10) were identified, indicating an intricate regulatory mechanism of LUCAT1 in TNBC. Indeed, LUCAT1 silencing led to mitigated cell growth, migration, and stem-like features in TNBC. This work sheds light on the LUCAT1 ceRNA network in TNBC and implies its involvement in TNBC growth and progression. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a common neurodegenerative disorder that presents a significant health concern, often leading to substantial cognitive decline among older adults. A prominent feature of AD is progressive dementia, which eventually disrupts daily functioning and the ability to live independently. A major challenge in addressing AD is its prolonged pre-symptomatic phase, which makes early detection difficult. Moreover, the disease's complexity and the inefficiency of current diagnostic methods impede the development of targeted therapies. Therefore, there is an urgent need to enhance diagnostic methodologies for detection and treating AD even before clinical symptoms appear. Exosomes are nanoscale biovesicles secreted by cells, including nerve cells, into biofluids. These exosomes play essential roles in the central nervous system (CNS) by facilitating neuronal communication and thus influencing major physiological and pathological processes. Exosomal cargo, particularly microRNAs (miRNAs), are critical mediators in this cellular communication, and their dysregulation affects various pathological pathways related to neurodegenerative diseases, including AD. This review discusses the significant roles of exosomal miRNAs in the pathological mechanisms related to AD, focusing on the promising use of exosomal miRNAs as diagnostic biomarkers and targeted therapeutic interventions for this devastating disease. [ABSTRACT FROM AUTHOR]

Since the introduction of the central dogma of molecular biology in 1958, various RNA species have been discovered. Messenger RNAs transmit genetic instructions from DNA to make proteins, a process facilitated by housekeeping non-coding RNAs (ncRNAs) such as small nuclear RNAs (snRNAs), ribosomal RNAs (rRNAs), and transfer RNAs (tRNAs). Over the past four decades, a wide array of regulatory ncRNAs have emerged as crucial players in gene regulation. In celebration of Cell 's 50th anniversary, this Review explores our current understanding of the most extensively studied regulatory ncRNAs—small RNAs and long non-coding RNAs (lncRNAs)—which have profoundly shaped the field of RNA biology and beyond. While small RNA pathways have been well documented with clearly defined mechanisms, lncRNAs exhibit a greater diversity of mechanisms, many of which remain unknown. This Review covers pivotal events in their discovery, biogenesis pathways, evolutionary traits, action mechanisms, functions, and crosstalks among ncRNAs. We also highlight their roles in pathophysiological contexts and propose future research directions to decipher the unknowns of lncRNAs by leveraging lessons from small RNAs. In this Review, Chen and Kim explore the exciting journey of discovering small and long non-coding RNAs. They also explain the current understanding as to how these RNAs are made, how they operate, and their pathophysiological roles and highlight key areas for future research to uncover more about these mysterious molecules. [ABSTRACT FROM AUTHOR]

Background: Despite advances in screening and therapy, breast cancer (BC) remains the predominant cancer in women globally. Dysregulation of microRNAs (miRNAs) is pivotal in carcinogenesis across various cancers, including BC. Evidence indicates that miR‐1307‐3p is upregulated in BC tumors, yet its target genes are not fully elucidated. This study aimed to explore how miR‐1307‐3p regulates BC proliferation, migration, invasion, and angiogenesis and to identify potential target genes. Methods: Basal miR‐1307‐3p levels were quantified in BC cell lines MDA‐MB‐231 and MCF‐7, as well as MCF‐10A using quantitative real‐time reverse transcription‐PCR (RT‐qPCR). The impact of miR‐1307‐3p inhibition on BC cell proliferation, migration, invasion, and angiogenesis was assessed. Nine miRNA‐target prediction databases identified potential miR‐1307‐3p targets. Target expression was validated using RT‐qPCR, Western blot, and dual‐luciferase reporter assays. MiR‐1307‐3p was overexpressed in MDA‐MB‐231 and MCF‐7 compared to MCF‐10A. Results: Inhibiting miR‐1307‐3p significantly reduced BC cell proliferation, migration, invasion, and angiogenesis. Bioinformatics analysis identified 17 potential miR‐1307‐3p targets, with protamine 2 (PRM2) overexpression confirmed via Western blot and dual‐luciferase assays. Conclusion: MiR‐1307‐3p overexpression in BC promotes proliferation, migration, invasion, and angiogenesis. PRM2 emerges as a novel miR‐1307‐3p target in BC. [ABSTRACT FROM AUTHOR]

Background: Osteoarthritis (OA) is a degenerative musculoskeletal disease that significantly impacts the quality of life. Currently, no validated biomarkers for early detection of OA are defined. The possibility of discovering OA biomarkers is the focus of this study. Methods: Human primary OA synovial cells (SVs), isolated from discarded joint tissue of patients with Kellgren & Lawrence score (KL) < 3, (mild/moderate) and KL ≥ 3 (severe), were characterized by FACS analysis. Through qRT-PCR and ELISA assays the inflammation, fibrosis status and the different miRNAs expression has been investigated. The role of miR-203a-3p and its precursors were evaluated through gain and loss of function study, IL-1β synoviocytes treatments and methylation analysis of miR203a promoter. The qRT-PCR analysis of miR203a-3p and pre-miR203a on plasma (isolated 24 h before surgery, 3 days and 1 month after surgery) and synovial fluid (recovered during the surgery) were done to support our in vitro data. Results: MiR203a-3p expression is inversely correlated with the aggressiveness of OA, modulating the expression of epithelial to mesenchymal transition (EMT) and pro-inflammatory factors, as well as regulating the expression of secreted protein acidic and rich in cysteine (SPARC) mRNA. Methylation analysis of the miR203a promoter and SVs IL-1β treatment's highlighted the impact of inflammation on miR203a-3p and pre-miR203a expression; as confirmed by both miRNAs detection in biological fluids derived from patients with severe OA. Conclusion: Our preliminary results suggest that miR-203a-3p might be a potential candidate for staging OA progression and a new protective/predictive biomarker for synovial OA degeneration. Further studies are needed to validate its potential impact on OA. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory condition and ranks as the fourth leading cause of mortality worldwide. Despite extensive research efforts, a reliable diagnostic or prognostic tool for COPD remains elusive. The identification of novel biomarkers may facilitate improved therapeutic strategies for patients suffering from this debilitating disease. MicroRNAs (miRNAs), which are small non-coding RNA molecules, have emerged as promising candidates for the prediction and diagnosis of COPD. Studies have demonstrated that dysregulation of miRNAs influences critical cellular and molecular pathways, including Notch, Wnt, hypoxia-inducible factor-1α, transforming growth factor, Kras, and Smad, which may contribute to the pathogenesis of COPD. Extracellular vesicles, particularly exosomes, merit further investigation due to their capacity to transport various biomolecules such as mRNAs, miRNAs, and proteins between cells. This intercellular communication can significantly impact the progression and severity of COPD by modulating signaling pathways in recipient cells. A deeper exploration of circulating miRNAs and the content of extracellular vesicles may lead to the discovery of novel diagnostic and prognostic biomarkers, ultimately enhancing the management of COPD. The current review focus on the pathogenic role of miRNAs and their exosomal counterparts in chest and respiratory diseases, centering COPD. [ABSTRACT FROM AUTHOR]

Background: Cerebral collateral circulation (CCC) considerably improves the prognosis of patients with symptomatic carotid stenosis (SCS). This study evaluated the diagnostic value of plasma microRNAs (miRNAs) in determining CCC status in patients with SCS. Methods: This single-center observational study enrolled patients with ≥50% carotid artery stenosis diagnosed using Doppler ultrasound. CCC was assessed using cerebrovascular digital subtraction angiography (DSA). Quantitative reverse transcription–polymerase chain reaction was used to determine the expression levels of plasma miRNAs. A multivariate logistic regression model and receiver operating characteristic (ROC) curve were used to analyze the diagnostic value of plasma miRNA expression in determining CCC status. Results: A total of 43 patients were enrolled (28 with CCC and 15 without CCC). The plasma expression levels of miR-126-3p, miR-132-3p, and miR-210-3p were significantly higher and those of miR-16-3p and miR-92-3p were significantly lower in patients with CCC. After adjusting for age, gender, drinking history, comorbidities and degree of SCS, miR-92a-3p, miR-126-3p, miR-132-3p, and miR-210-3p were found to be significantly associated with CCC establishment (p < 0.05). ROC curve analysis indicated a high diagnostic value of these miRNAs in determining CCC status [area under the curve (AUC): 0.918–0.965], with miR-126-3p exhibiting the highest predictive performance (AUC: 0.965). Subgroup analysis revealed that patients with CCC who had 50%–70% stenosis showed significantly higher expression level of miR-126-3p, whereas those with CCC who had 70%–99% stenosis showed significantly higher expression levels of miR-126-3p, miR-132-3p, and miR-210-3p as well as significantly lower expression levels of miR-15a-3p, miR-16-3p, and miR-92a-3p. Conclusion: The results indicate that these six plasma miRNAs have promising diagnostic value in determining CCC status in varying degrees of SCS. These miRNAs can serve as biomarkers for CCC status following SCS, with miR-126-3p showing the strongest positive correlation. [ABSTRACT FROM AUTHOR]

Prostate cancer is the most common solid malignant tumor in men, characterized by high morbidity and mortality. While current screening tools, such as prostate-specific antigen (PSA) testing and digital rectal examination, are available for early detection of prostate cancer, their sensitivity and specificity are limited. Tissue puncture biopsy, although capable of offering a definitive diagnosis, has poor positive predictive rates and burdens the patient more. Therefore, more reliable molecular diagnostic tools for prostate cancer urgently need to be developed. In recent years, microRNAs (miRNAs) have attracted much attention in prostate cancer research. miRNAs are extensively engaged in biological processes such as cell proliferation, differentiation, apoptosis, migration, and invasion by modulating gene expression post-transcriptionally. Dysregulation of miRNA expression in cancer is considered a critical factor in tumorigenesis and progression. This review first briefly introduces the biogenesis of miRNAs and their functions in cancer, then focuses on tumor-promoting miRNAs and tumor-suppressor miRNAs in prostate cancer. Finally, the potential application of miRNAs as multifunctional tools for cancer diagnosis, prognostic assessment, and therapy is discussed in detail. The concluding section summarizes the major points of the review and the challenges ahead. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons. Recent research has emphasized a significant correlation between microRNAs (miRNAs) and PD. To identify key research areas, provide a comprehensive overview of current research in various fields, and propose potential directions for future studies, a bibliometric analysis was conducted on the involvement of miRNAs in Parkinson's disease from 2014 to 2023. Methods: Relevant literature records were collected from the Web of Science Core Collection on February 29, 2024. Subsequently, the data underwent analysis using the Bibliometrix R package and VOSviewer (version 1.6.19). Results: The annual scientific publications on miRNAs and Parkinson's disease demonstrated an increasing trend, with an annual growth rate of 12.67%. China, the United States, and India emerged as the top three most productive countries/regions. The University of Barcelona had the highest annual publications, followed by Central South University and the Helmholtz Association. The INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES held the top position in terms of H-index and total citations, reflecting its extensive influence and prolific publication output. Kim, J., Junn, E., Hébert, S.S., and Doxakis, E. were the most frequently co-cited authors in the field. Based on the analysis of keywords, the most frequently occurring terms included "alpha-synuclein," "neurodegenerative disease," "exosome," "neuroinflammation," "oxidative stress," "autophagy," and "amyotrophic lateral sclerosis," which have emerged as prominent research topics. Concurrently, there has been notable interest in topics such as "ceRNA," "lncRNAs," "mitochondrial dysfunction," and "circular RNA." Conclusion: This study focused on identifying emerging trends and critical research topics in the bibliometric analysis of microRNAs related to Parkinson's disease. These findings highlight the diverse research landscape and evolving trend of miRNA-related research in PD. The field of miRNA research in Parkinson's disease is actively exploring the underlying mechanisms of miRNA function, identifying potential diagnostic markers, and developing innovative therapeutic strategies. The results of our study offer significant contributions to researchers' ability to track contemporary developments and guide the trajectory of future research in this domain. [ABSTRACT FROM AUTHOR]

Objective To examine the differential expression of microRNA-143-3p (miR-143-3p) in gliomas and normal brain tissues, investigating its association with glioma clinicopathological features and its potential biological effects on glioma cell behavior. Methods Fifty-five glioma tissue samples and fifteen normal brain tissue samples from patients with traumatic brain injury or hemorrhage were collected from October 2021 to October 2023 at the Fourth Hospital of Hebei Medical University. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to determine miR-143-3p levels in glioma and normal brain tissues, as well as in human astrocytes and glioma cell lines (198, U87, U251). The impact of miR-143-3p overexpression on glioma cell proliferation, invasion, migration, cell cycle progression, and apoptosis was evaluated using scratch assays, Transwell assays, CCK-8 assays, and flow cytometry. Results miR-143-3p expression was significantly lower in glioma tissues compared to normal brain tissues (P< 0.0001). Low miR-143-3p expression correlated with glioma grade (P<0.001) but showed no significant association with age, gender, or KPS score (P>0.05). Similarly, miR-1433p expression in glioma cell lines (T98, U87, U251) was significantly lower than in human astrocytes (P<0.01). Overexpression of miR-143-3p markedly inhibited glioma cell proliferation, migration, and invasion (P<0.01), induced cell cycle arrest in the G0/G1 phase, decreased proliferation indices, and significantly increased apoptosis rates (P<0.01). Conclusion miR-143-3p is downregulated in glioma tissues, and its reduced expression is associated with glioma malignancy. miR-143-3p inhibits glioma cell proliferation, invasion, and migration while promoting apoptosis, suggesting its potential as a therapeutic target in glioma. [ABSTRACT FROM AUTHOR]

Lung cancer remains the cancer with the highest mortality worldwide, largely due to a limited understanding of the precise molecular mechanisms that drive its progression. microRNAs (miRNAs) have emerged as crucial regulators of lung cancer progression by influencing key cellular processes, notably the epithelial–mesenchymal transition (EMT). EMT is a complex and potentially reversible process where epithelial cells lose their polarity and adhesion, reorganize their cytoskeleton, and transition to a mesenchymal phenotype, enhancing their migratory and invasive capacities. While EMT plays an essential role in normal physiological contexts such as tissue development and wound healing, it is also a critical mechanism underlying the progression and metastasis of lung cancer. This review aims to summarize the latest research findings on the role of endogenous and exosome-derived microRNAs in regulating EMT in lung cancer, focusing on studies conducted over the past five years. It also provides an overview of EMT's essential molecular mechanisms to better understand how miRNAs regulate EMT in lung cancer. [ABSTRACT FROM AUTHOR]

(1) Background: Endometriosis is a highly prevalent gynecological disease affecting 10% of women of reproductive age worldwide. miRNAs may play a role in endometriosis, though their exact function remains unclear. This study aimed to identify differentially expressed miRNAs in endometriosis and study their functions in the disease. (2) Methods: Endometrial tissue was collected from women with endometriosis (n = 15) and non-endometriosis controls (n = 17). Dysregulated miRNAs were identified through small RNA-sequencing, and their biological significance was explored by target gene prediction and pathway analysis. Selected miRNAs were examined in paired ectopic endometriomas and eutopic endometrium (n = 10) using qRT-PCR. Their roles in cell migration and proliferation were further examined in vitro using functional assays. To identify potential target genes, we performed mRNA sequencing on transfected cells and the endometrioma cohort. (3) Results: We identified 14 dysregulated miRNAs in the eutopic endometrium of women with endometriosis compared to endometrial tissue from women without endometriosis. Pathway analysis indicated enrichment in cell migration and proliferation-associated pathways. Further ex vivo studies of miR-193b-5p and miR-374b-5p showed that both miRNAs were upregulated in endometrioma. Overexpression of these two miRNAs in vitro inhibited cell migration, and mRNA sequencing revealed several migration-related genes that are targeted by these miRNAs. (4) Conclusions: Our study identified two key endometrial miRNAs that may be involved in the pathogenesis of endometriosis by regulating cell migration. [ABSTRACT FROM AUTHOR]

Simple Summary: Brassica yellows virus, transmitted by the green peach aphid in a persistent circulative manner, is a newly identified polerovirus that is widespread in China. To investigate the molecular characterization of microRNAs (miRNAs) in aphids responding to BrYV stress, non-viruliferous and viruliferous aphids were inoculated to turnip plants (treatment one) or Arabidopsis thaliana (treatment two) for 72 h, prior to small RNA sequencing. Numerous known and novel miRNAs in aphids were identified from both treatments. Notably, more differentially expressed miRNAs were identified in viruliferous aphids in the comparisons of treatment two vs. treatment one, with the target genes primarily involved in Peroxisome, neuroactive ligand–receptor interaction, and metabolism of xenobiotics by cytochrome P450 pathways. These findings enhance our understanding of the regulatory role of BrYV on miRNAs in Myzus persicae and provide crucial clues for screening key miRNAs involved in virus circulation in aphids. microRNAs (miRNAs) influence many biological processes at the post-transcriptional level. However, the molecular characterization of miRNAs in the Myzus persicae response to Brassica yellows virus (BrYV) stress remains unclear. In this study, we present the results of miRNA profiling in Myzus persicae under two different treatments: treatment one (raised on turnip plants), and treatment two (raised on Arabidopsis thaliana). A total of 72 known and 113 novel mature miRNAs were identified in both non-viruliferous and viruliferous aphids, under treatment one. In treatment two, 72 known and 112 novel mature miRNAs were identified in BrYV-free aphids; meanwhile, 71 known and 115 novel miRNAs were identified in BrYV-carrying aphids. Moreover, eight upregulated and four downregulated miRNAs were identified in viruliferous aphids under treatment two, whereas only two miRNAs were differentially expressed under treatment one. These results indicated the relative BrYV level could influence miRNA expression in aphids. KEGG enrichment analysis showed the predicted genes targeted by differentially expressed miRNAs were primarily involved in Peroxisome, neuroactive ligand–receptor interaction, and metabolism of xenobiotics by cytochrome P450 pathways. Taken together, these findings reveal the effect of BrYV on miRNAs in Myzus persicae and provide key clues for further studies on the molecular mechanisms of BrYV transmission via aphids. [ABSTRACT FROM AUTHOR]

Objective To investigate the clinical diagnostic value of routine electroencephalogram (EEG) combined with serum miR-146a and miR-129-5p levels in drug-resistant epilepsy. Methods Sixty patients with refractory epilepsy admitted to our hospital from June 2021 to June 2023 were included in the refractory epilepsy group, and 40 healthy volunteers were included in the control group. Human microvascular endothelial drug-resistant cells (HBMECs) continuously exposed to PHT2 were cultured in vitro and transfected with miR-NC (the miR-NC group), miR-146a mimics (the miR146a mimics group) and miR-129-5p mimics (the miR-129-5p mimics group), respectively. Western blod assay was used to detect the expression of high-mobility group protein B1 (HMGB1) in each group. Serum miR-146a and miR-129-5p levels were detected by fluorescent quantitative PCR (polymerase chain reaction), and serum HMGB1 protein expression was detected by Western blod assay. The sensitivity, specificity and accuracy of routine EEG, serum miR-146a and miR-129-5p levels and combined diagnosis of drug-resistant epilepsy were evaluated using the comprehensive consultation results of several expert physicians as the gold standard, and ROC curves were drawn. Results Compared with the control group, the expression of HMGB1 was significantly decreased in the drug-resistant group. Compared with the miR-NC group, HMGB1 expression was significantly decreased in the miR-129-5p mimics group and the miR-146a mimics group (P＜0.05). Compared with the healthy group, the serum HMGB1 protein expression was down-regulated and miR-146a and miR-129- 5p expression levels were significantly up-regulated in the refractory epilepsy group. ROC curve analysis indicated that the area under the curve, sensitivity, specificity and accuracy of conventional EEG combined with serum miR-146a and miR129-5p levels were higher in the diagnosis of refractory epilepsy than that of single diagnostic method. Conclusion The combination of routine EEG and serum miR-129-5p and miR-146a levels can provide help for the diagnosis of drug-resistant patients. [ABSTRACT FROM AUTHOR]

Background: In recent years, liquid biopsy has emerged as a promising tool for the diagnosis and prognosis of numerous diseases, including cancer. Among the biomolecules analyzed in liquid biopsies are plasma circulating microRNAs (miRNAs), small non-coding RNAs that have proven to be crucial in the regulation of gene expression and the pathobiology of different health conditions, making them useful as biomarkers. However, variations in preanalytical conditions during biospecimen collection and processing can affect the analytical results. Objectives: Herein, we determined how the type of collection tube, the number of centrifugations, and the degree of hemolysis can affect plasma circulating miRNA levels. Methods: A cohort of 11 healthy donors was included. Whole blood was collected and handled in three different conditions, and miRNAs levels were analyzed using quantitative RT-PCR. Results: Our results show that the differences in the type of preservative tubes influence hemolysis, measured as OD at 414 nm. Moreover, the number of centrifugations performed also altered miRNAs levels, increasing or decreasing them depending on the miRNA analyzed. Hence, our study shows that alterations in preanalytical conditions affect miRNAs levels, particularly the number of centrifugations and the type of collection tubes. Conclusions: In our work, we highlight the importance of registering the preanalytical conditions in a standardized way that might be considered when analytical results are obtained. [ABSTRACT FROM AUTHOR]

Background and aim: MicroRNAs (miRs) are now a well-known subject in various tumor genesis and are studied as early diagnostic biomarker. Many arrays of miRs were incorporated in the pathogenesis of HCV-related hepatocellular carcinomas (HCV-HCC). In this respect, we aimed to evaluate the diagnostic role of circulating miR-21, miR-122, and miR-222 in Egyptian patients with HCV-HCC. Patient and methods: Between June 2018 and April 2019, a cross-sectional comparative study was designed to evaluate the circulating miR-21, miR-122, and miR-222 by quantitative Real-Time PCR. For analytical purposes, patients were categorized into three groups: chronic HCV group (CHC-group, n = 22), HCV-related liver cirrhosis (LC-group, n = 22), and HCV-related hepatocellular carcinoma (HCV-HCC-group, n = 54). Results: Serum levels of miR-21 and miR-222 increased with the progressive course from CHC to LC and HCC; p <.001. Serum levels of miR-122 in HCC patients were significantly lower than non-HCC patients (CHC and LC patients, n = 44); p <.001. However, the differences in levels of serum miR-122 between CHC and LC were not statistically significant; P = 0.8. ROC curve analysis showed that the sensitivity and specificity of miR-21 were 61.1% and 95.5%, miR-222 were 71.7% and 93.2%, and miR-122 were 98.2% and 100%. The positive predictive value for miRNA-21, miRNA-122, and miRNA-222 were 13.4%, 93.3%, and 10.5% respectively. The Negative predictive value for miRNA-21, miRNA-122, and miRNA-222 were 94.3%, 97.8%, and 92.7% respectively. Conclusion: MiR-21 and miR-222 could be potential markers for advanced liver damage, while miR-122 had the best diagnostic accuracy and could be a promising marker for detection of HCC. [ABSTRACT FROM AUTHOR]