Germ cell development and gamete production in animals require small RNA pathways. While studies indicate that microRNAs (miRNAs) are necessary for normal sperm production and function, the specific roles for individual miRNAs are largely unknown. Here, we use small RNA sequencing of dissected gonads and functional analysis of new loss of function alleles to identify functions for miRNAs in the control of fecundity and sperm production in Caenorhabditis elegans (C. elegans) males and hermaphrodites. We describe a set of 29 male gonad-enriched miRNAs and identify a set of individual miRNAs (mir-58.1 and mir-235) and a miRNA cluster (mir-4807-4810.1) that are required for optimal sperm production at 20°C and a set of miRNAs (mir-49, mir-57, mir-83, mir-261, and mir-357/358) that are required for sperm production at 25°C. We observed defects in meiotic progression in mutants missing mir-58.1, mir-83, mir-235, and mir-4807-4810.1, which may contribute to the observed defects in sperm production. Further, analysis of multiple mutants of these miRNAs suggested genetic interactions between these miRNAs. This study provides insights on the regulatory roles of miRNAs that promote optimal sperm production and fecundity in males and hermaphrodites.

Acute promyelocytic leukemia (APL) is marked by a block at the promyelocyte stage. Treatments like ATRA and ATO face resistance and relapse issues. Plastrum testudinis, a traditional Chinese medicine, may offer therapeutic potential. This study investigated xtr-miR-22-3p from P. testudinis for treating APL. High expression of xtr-miR-22-3p was confirmed, with target prediction indicating interactions with key genes, including PML. xtr-miR-22-3p reduced HL-60 leukemia cell growth, altered the cell cycle, and selectively inhibited HL-60 proliferation while promoting BMSC growth, suggesting its potential as a targeted APL therapy.

Microglia are immunocompetent cells that are present in the retina and central nervous system, and are involved in the development maintenance and immune functions in these systems. Developing from yolk sac-primitive macrophages, they proliferate in the local tissues during the embryonic period without resorting to the production from the hematopoietic stem cells, and are critical in sustaining homeostasis and performing in disease and injury; they have morphological characteristics and distinct phenotypes according to the microenvironment. Microglia are also present in close association with resident cells in the retina where they engage in synapse formation, support normal functions, as well as immune defense. They are involved in the development of numerous neurodegenerative and ophthalmic diseases and act as diversity shields and triggers. Noncoding ribonucleic acids (ncRNAs) refer to RNA molecules synthesized from the mammalian genome, and these do not have protein-coding capacity. These ncRNAs play a role in the regulation of gene expression patterns. ncRNAs have only been recently identified as vastly significant molecules that are involved in the posttranscriptional regulation. Microglia are crucial for brain health and functions and current studies have focused on the effects caused by ncRNA on microglial types. Thus, the aim of the review was to provide an overview of the current knowledge about the regulation of microglial phenotypes by ncRNAs.

UNASSIGNED: MicroRNAs (miRNAs) show promise as blood-based tumor markers for germ cell tumors (GCTs), with miRNA-371-3p being the most studied. The marginal benefit of including other candidate miRNAs to aid with the management of testicular GCTs remains unclear.
UNASSIGNED: To assess the performance of our combined miRNA assay (371a-3p and 372-3p) in patients with clinically localized testicular masses.
UNASSIGNED: This was a retrospective review of patients prospectively enrolled in an ongoing protocol collecting serum miR-371a-3p and miR-372-3p levels (together, Memorial Sloan Kettering Cancer Center [MSK] miRNA assay [MMA]) in patients with a suspected or diagnosed testicular GCT.
UNASSIGNED: The coprimary outcomes of interest were sensitivity and specificity of miR-371a-3p and 372-3p, individually and together, to detect nonteratomatous GCTs in the orchiectomy specimen. Secondary outcomes included additional assay diagnostic parameters, the relationship of patient and disease factors with variations in miRNA levels, and temporal patterns of miRNA normalization after orchiectomy.
UNASSIGNED: Sixty-two patients were included, 52 had a viable GCT at orchiectomy, and ten had no cancer or a non-GCT. Forty-six patients with a GCT had positive preorchiectomy MMA (sensitivity 88.5% [95% confidence interval {CI}: 79.8, 97.2]), and one patient had positive preorchiectomy MMA but no GCT (specificity 90.0% [95% CI: 71.4, 100]). The diagnostic performance of miR-371a-3-p and miR-372-3p was similar. The time for miRNA to decrease to undetectable levels varied, with some patients having positive levels up to 3 wk after orchiectomy.
UNASSIGNED: The biomarkers miR-371a-3p and miR-372-3p demonstrated high sensitivity and specificity for localized testicular GCTs, but causes of variation in relative miRNA levels and time to normalization for individual patients remain unclear.
UNASSIGNED: We studied the ability of the blood-based biomarkers miR-371a-3p and miR-372-3p to detect testicular cancer (germ cell tumors) in patients with small testicular masses. We found that together and individually these were sensitive and specific for testicular cancer.

MicroRNAs (miRNAs) are regulators of gene expression, and their dysregulation is linked to cancer and other diseases, making them important therapeutic targets. Several strategies for targeting and modulating miRNA activity are being explored. For example, steric blocking antisense oligonucleotides (ASOs) can reduce miRNA activity by either blocking binding sites on specific mRNAs or base-pairing to the miRNA itself to prevent its interaction with the target mRNAs. ASOs have been less explored as a tool to elevate miRNA levels, which could also be beneficial for treating disease. In this study, using the PKD1/miR-1225 gene locus as an example, where miR-1225 is located within a PKD1 intron, we demonstrate an ASO-based strategy that increases miRNA abundance by enhancing biogenesis from the primary miRNA transcript. Disruptions in PKD1 and miR-1225 are associated with autosomal dominant polycystic kidney disease (ADPKD) and various cancers, respectively, making them important therapeutic targets. We investigated PKD1 sequence variants reported in ADPKD that are located within the sequence shared by miR-1225 and PKD1, and identified one that causes a reduction in miR-1225 without affecting PKD1. We show that this reduction in miR-1225 can be recovered by treatment with a steric-blocking ASO. The ASO-induced increase in miR-1225 correlates with a decrease in the abundance of predicted miR-1225 cellular mRNA targets. This study demonstrates that miRNA abundance can be elevated using ASOs targeted to the primary transcript. This steric-blocking ASO-based approach has broad potential application as a therapeutic strategy for diseases that could be treated by modulating miRNA biogenesis.

Chronic obstructive pulmonary disease (COPD) is a deteriorating condition triggered by various factors, such as smoking, free radicals, and air pollution. This worsening disease is characterized by narrowing and thickening of airways, painful cough, and dyspnea. In COPD, numerous genes as well as microRNA (miRNA) play a significant role in the pathogenesis of the disease. Many in vivo and in vitro studies suggest that upregulation or suppression of certain miRNAs are effective treatment options for COPD. They have been proven to be more beneficial than the current symptomatic treatments, such as bronchodilators and corticosteroids. MiRNAs play a crucial role in immune cell development and regulate inflammatory responses in various tissues. MiRNA treatment thus allows for precision therapy with improved outcomes. Nanoparticle drug delivery systems such as polymeric nanoparticles, inorganic nanoparticles, dendrimers, polymeric micelles, and liposomes are an efficient method to ensure the biodistribution of the miRNAs to the target site. Identification of the right nanoparticle depending on the requirements and compatibility is essential for achieving maximum therapeutic effect. In this review, we offer a thorough comprehension of the pathology and genetics of COPD and the significance of miRNAs concerning various pathologies of the lung, as potential targets for treating the disease. The present review offers the latest insights into the nanoparticle drug delivery systems that can efficiently carry and deliver miRNA or antagomirs to the specific target site and hence help in effective management of COPD.

Mesenchymal stem cells (MSCs) have gained attention as a promising therapeutic approach in both preclinical and clinical osteoarthritis (OA) settings. Various joint cell types, such as chondrocytes, synovial fibroblasts, osteoblasts, and tenocytes, can produce and release extracellular vesicles (EVs), which subsequently influence the biological activities of recipient cells. Recently, extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have shown the potential to modulate various physiological and pathological processes through the modulation of cellular differentiation, immune responses, and tissue repair. This review explores the roles and therapeutic potential of MSC-EVs in OA and rheumatoid arthritis, cardiovascular disease, age-related macular degeneration, Alzheimer\'s disease, and other degenerative diseases. Notably, we provide a comprehensive summary of exosome biogenesis, microRNA composition, mechanisms of intercellular transfer, and their evolving role in the highlight of exosome-based treatments in both preclinical and clinical avenues.

OBJECTIVE: MicroRNAs (miRNAs) are non-coding RNAs which have attracted attention as biomarkers in a variety of diseases. However, extensive unbiased analysis of miRNA in vitreous humor of sarcoidosis patients has not been reported. In the present study, we comprehensively analyzed the dysregulated miRNAs in ocular sarcoidosis to search for potential biomarkers.
METHODS: This study included seven patients diagnosed with ocular sarcoidosis (five definite and two presumed). Five patients with unclassified uveitis and 24 with non-inflammatory diseases served as controls. MicroRNA expression levels in vitreous humor samples were measured by microarray, and differentially expressed miRNAs between sarcoidosis and other diseases were explored. Next, pathway enrichment analysis was performed to evaluate the functions of the dysregulated miRNAs, and machine learning was used to search for candidate biomarkers.
RESULTS: A total of 614 upregulated miRNAs and 8 downregulated miRNAs were detected in vitreous humor of patients with ocular sarcoidosis compared with patients with unclassified uveitis and non-inflammatory diseases. Some dysregulated miRNAs were involved in the TGF-β signaling pathway. Furthermore, we identified miR-764 as the best predictor for ocular sarcoidosis using Boruta selection.
CONCLUSIONS: In this study, comprehensive miRNA analysis of vitreous humor samples identified dysregulated miRNAs in ocular sarcoidosis. This study suggests new insights into molecular pathogenetic mechanisms of sarcoidosis and may provide useful information toward developing novel diagnostic biomarkers and therapeutic targets for sarcoidosis.

Molecular-profiling-based cancer diagnosis has significant implications for predicting disease prognosis and selecting targeted therapeutic interventions. The analysis of cancer-derived extracellular vesicles (EVs) provides a noninvasive and sequential method to assess the molecular landscape of cancer. Here, we developed an all-in-one fusogenic nanoreactor (FNR) encapsulating DNA-fueled molecular machines (DMMs) for the rapid and direct detection of EV-associated microRNAs (EV miRNAs) in a single step. This platform was strategically designed to interact selectively with EVs and induce membrane fusion under a specific trigger. After fusion, the DMMs recognized the target miRNA and initiated nonenzymatic signal amplification within a well-defined reaction volume, thus producing an amplified fluorescent signal within 30 min. We used the FNRs to analyze the unique expression levels of three EV miRNAs in various biofluids, including cell culture, urine, and plasma, and obtained an accuracy of 86.7% in the classification of three major breast cancer (BC) cell lines and a diagnostic accuracy of 86.4% in the distinction between patients with cancer and healthy donors. Notably, a linear discriminant analysis revealed that increasing the number of miRNAs from one to three improved the accuracy of BC patient discrimination from 78.8 to 95.4%. Therefore, this all-in-one diagnostic platform performs nondestructive EV processing and signal amplification in one step, providing a straightforward, accurate, and effective individual EV miRNA analysis strategy for personalized BC treatment.

Screening plays a crucial role in the early detection of colorectal cancer, greatly reducing mortality rates. The objective of this study was to identify a non-invasive diagnostic method utilizing serum microRNA expression for the diagnosis of colorectal cancer patients. The study consisted of three stages. In the first stage, 129 patients with colorectal cancer and 129 normal subjects were recruited as the training set for the development of a blood miRNA panel. The second stage involved recruiting 200 patients from each group as the validation cohort. Finally, a blinded study was conducted in the third stage, with 260 patients recruited to determine the predictive value of our miRNA panel. Serum samples were prospectively collected from colorectal cancer patients and normal subjects between 2017 and 2021 at Queen Mary Hospital in Hong Kong. Quantitative PCR was utilized to detect the serum levels of candidate microRNAs, and a multiple linear regression model was employed to formulate a serum microRNA panel for diagnosing colorectal cancer patients. The performance of the panel was evaluated using ROC analysis. Our study showed that the values of three pairs of serum microRNAs, namely miR-106b-5p/miR-1246, miR-106b-5p/miR-16 and miR-106b-5p/miR-21-5p, exhibited statistically significant differences between colorectal cancer patients and normal subjects. A serum microRNA panel formulated from these three pairs of microRNAs demonstrated high accuracy in diagnosing colorectal cancer patients from normal subjects, with an AUC of approximately 0.9. The serum miRNA test proved to be a feasible and promising non-invasive biomarker for the diagnosis of colorectal cancer patients in comparison to normal subjects.