MicroRNAs (miRNAs) are short non‑coding RNAs, which perform a key role in cellular differentiation and development. Most human diseases, particularly cancer, are linked to miRNA functional dysregulation implicated in the expression of tumor‑suppressive or oncogenic targets. Cancer hallmarks such as continued proliferative signaling, dodging growth suppressors, invasion and metastasis, triggering angiogenesis, and avoiding cell death have all been demonstrated to be affected by dysregulated miRNAs. Thus, for the treatment of different cancer types, the detection and quantification of this type of RNA is significant. The classical and current methods of RNA detection, including northern blotting, reverse transcription‑quantitative PCR, rolling circle amplification and next‑generation sequencing, may be effective but differ in efficiency and accuracy. Furthermore, these approaches are expensive, and require special instrumentation and expertise. Thus, researchers are constantly looking for more innovative approaches for miRNA detection, which can be advantageous in all aspects. In this regard, an RNA manipulation tool known as the CRISPR and CRISPR‑associated sequence 13 (CRISPR/Cas13) system has been found to be more advantageous in miRNA detection. The Cas13‑based miRNA detection approach is cost effective and requires no special instrumentation or expertise. However, more research and validation are required to confirm the growing body of CRISPR/Cas13‑based research that has identified miRNAs as possible cancer biomarkers for diagnosis and prognosis, and as targets for treatment. In the present review, current updates regarding miRNA biogenesis, structural and functional aspects, and miRNA dysregulation during cancer are described. In addition, novel approaches using the CRISPR/Cas13 system as a next‑generation tool for miRNA detection are discussed. Furthermore, challenges and prospects of CRISPR/Cas13‑based miRNA detection approaches are described.

Mitochondria play crucial roles in energy production, metabolism regulation, and cell death. Mitochondrial dysfunction is associated with many diseases, including cancers, aging, and neurodegenerative disorders. Consequently, developing methods for mitochondrial regulation and treating related diseases has garnered significant interest in biological and medical research. Here, a smart framework nucleic acid (FNA) strategy is presented for mitochondrial interference and targeted cell elimination. Our approach involves the design of tetrahedral DNA nanostructures (TDNs) modified with triphenylphosphine and single-stranded DNA sequences responding to specific nucleic acid biomarkers (e.g., microRNAs) presented in target cells. The interlinked DNA networks, formed in situ responding to specific biomarkers, enable targeting and enveloping of the mitochondria, leading to mitochondrial fragmentation and dysfunction. It is demonstrated that TDN-based FNAs targeted the cancer-associated microRNA (miR-21) may enhance the efficacy of cancer therapy by disrupting mitochondrial function, while also serving as carriers of anti-cancer drugs to reduce the side effects. Additionally, FNAs targeting the senescence-associated microRNA (miR-34a) specifically eliminate senescent cells in both cell and Caenorhabditis elegans models, thereby improving overall cell viability within mixed cell populations. This programmable and functionalized TDN-based platform opens new avenues for advancing anti-aging research and treating various diseases by achieving targeted cell elimination through mitochondrial interference.

There is a critical need for inclusive diagnostic platforms to enhance the accuracy of early breast cancer detection. Dysregulated microRNA-1246 (miR-1246), closely linked to the disease progression and recurrence, has emerged as a promising diagnostic and prognostic biomarker for BC. However, achieving simple, rapid, and ultrasensitive quantification of serum miRNAs remains significant challenge. In this study, we present an innovative detection platform triggered by endogenous DNA repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1). This platform utilizes an oligonucleotide probe with variable modified AP sites (denoted as AOP) coupled with graphene oxide (GO) for quantifying miR-1246. Our in vitro experiments reveal that the proposed method employing the AOP2 probe with two AP sites exhibits exceptional selectivity and sensitivity. The method achieves a detection limit as low as 2.3 pM towards miR-1246, which is approximately 260-fold more sensitive than the enzyme-free system. RT-qPCR experiments further validate the accuracy and practicability of the AOP2-based platform. In clinical trials, our platform has successfully differentiated between BC patients and normal healthy controls. In conclusion, we have established an integrated biosensing technology for PCR-free, non-invasive liquid biopsies of miR-1246, offering a promising approach for BC diagnosis.

This work aimed to evaluate the modulating effect of polyunsaturated fatty acids omega-3 and omega-6 on the expression of TP53 and specific primiRNAs 34 b/c in the development of premalignant characteristics in tongue epithelial dysplasias in-vivo experimental models DESIGN: BALB/c mice were divided into two diet groups: fish oil rich in omega-3 and corn oil rich in omega-6. Tongue dysplasia was generated by applying a 0.5 % solution of 7,12-dimethylbenzantracene (DMBA) in acetone. After sacrificing, the animals were assessed for omega-6 and omega-3, TP53/Ki67 immunostaining, Trp53R270H mutations, and primiRNA 34 b/c expression.

Mice fed omega-6 showed higher dysplasias and Ki67 immunostaining percentages than those fed omega-3-rich oils. Furthermore, mice fed with corn oil rich in omega-6 showed significantly high average arachidonic-acid values, while the group fed cod oil rich in omega-3 showed substantially higher average values of Ecosapentanoic acid and Docosahexanoic acid in tongue tissue cell membranes. The primiRNA-34 b/c was upregulated in animals fed corn oil, enriched-omega-6 at 90 days.

Our findings suggest that dietary lipids influence the development of DMBA-induced premalignant features on the tongue of mice; therefore, a low intake of omega-6-rich oils and a higher intake of omega-3 could be recommended for preventing features similar to mucosal dysplasia, which could be an important preventive strategy.

Prostate cancer (PC) ranks as the fifth major cause of cancer-related fatalities globally. Exploring new methods with high efficacy and low side effects by using new compounds is always desired. Tea is considered the second most commonly consumed beverage among the population of the world. Polyphenols (or catechins) in green tea play a significant role in cellular signaling pathways. Herein, we evaluate the effects of green tea extract on suppression of cellular proliferation through testing the expression of miR-34a in PC3 prostate cancer cells. In this respect, PC3 prostate cancer cells were cultured and treated with green tea extract for 48 h. By using the qRT-PCR method, the expression of miR-34a was analyzed. Moreover, the expression of key proteins to regulate cellular proliferation, such as prostate specific antigen (PSA), AKT, cyclin dependent kinase 1 (CDK1), cyclin B1, c-Myc, p53, and phospho-androgen receptor (p-AR) was evaluated by using western blot. Our results indicated the induction of miR-34a, p53, and the inhibition of cyclin B1, p-AR, CDK1, p-AKT, PSA, c-Myc, and p-CDK1. Our findings can be used to design anti-tumor regimens that utilize natural product ingredients. However, additional research will be needed to identify anticancer activities of green tea via miR-34a in prostate cancer cells.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is emerging as the leading cause of chronic liver disease worldwide, reflecting the global epidemics of obesity, metabolic syndrome, and type 2 diabetes. Beyond its strong association with excess adiposity, MASLD encompasses a heterogeneous population that includes individuals with normal body weight ("lean MASLD") highlighting the complexity of its pathogenesis. This disease results from a complex interplay between genetic susceptibility, epigenetic modifications, and environmental factors, which converge to disrupt metabolic homeostasis. Adipose tissue dysfunction and insulin resistance trigger an overflow of lipids to the liver, leading to mitochondrial dysfunction, oxidative stress, and hepatocellular injury. These processes promote hepatic inflammation and fibrogenesis, driven by cross talk among hepatocytes, immune cells, and hepatic stellate cells, with key contributions from gut-liver axis perturbations. Recent advances have unraveled pivotal molecular pathways, such as transforming growth factor-β signaling, Notch-induced osteopontin, and sphingosine kinase 1-mediated responses, that orchestrate fibrogenic activation. Understanding these interconnected mechanisms is crucial for developing targeted therapies. This review integrates current knowledge on the pathophysiology of MASLD, emphasizing emerging concepts such as lean metabolic dysfunction-associated steatohepatitis (MASH), epigenetic alterations, hepatic extracellular vesicles, and the relevance of extrahepatic signals. It also discusses novel therapeutic strategies under investigation, aiming to provide a comprehensive and structured overview of the evolving MASLD landscape for both basic scientists and clinicians.

Ovarian and cervical cancers are the two most frequent kind of gynaecological cancers (GCs). In spite of advances in prevention, screening and treatment, cervical cancer still leads to an increased morbidity and mortality worldwide. Ovarian cancer is often detected at a late stage, which significantly reduces the effectiveness of available treatments. Therefore, novel methods are desperately needed to improve the clinical care of GC patients. MicroRNAs, also known as short noncoding RNAs (miRNAs/miRs), are a diverse group of RNAs with a length of 22 nucleotides. These typically cause translational repression and mRNA degradation by interacting with target mRNAs' 3' untranslated region (3'-UTR), together with other regions and gene promoters. Under certain conditions, they are also able to activate translation or regulate transcription. It has been demonstrated that miRNAs are crucial to several biological processes leading to tumorigenesis, including GCs. Recent research has shown that miR-9 affects carcinogenesis. In this review, we will provide an overview of current research on the potential utility of miR-9 in the diagnosis, prognosis, and therapy of ovarian and cervical malignancies.

The aim of this study was to evaluate the association between miR-34 family expression and overall survival (OS) and progression-free survival (PFS) in women with ovarian cancer.

Literature searches were conducted using databases such as PubMed, Cochrane Library, EMBASE, Web of Science, Wanfang, and CNKI to identify studies reporting pooled hazard ratios (HRs) and 95% confidence intervals (CIs) examining the relationship between miR-34 family expression and overall survival (OS) or progression-free survival (PFS) in female patients with ovarian cancer. All potentially relevant studies were assessed and then pooled.

There were a total of seven literatures included in this systematic review and meta-analysis, which included 672 women. There was a significant improvement in survival for women with ovarian cancer when miR-34s expression was higher (OS, HR = 0.70, 95% CI:0.57-0.86; PFS, HR = 0.48, 95% CI:0.31-0.75). A subgroup analysis of miR-34 family members showed that differences between groups greatly affected PFS (HR = 0.50, 95% CI: 0.40-0.63).

Based on the results of this review, it appears that ovarian cancer women with high expression of miR-34s may have a better chance of surviving.Systematic Review Registration: PROSPERO (CRD42024499203).

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024499203.

MicroRNAs (miRNAs) are short non-coding RNAs, that regulate gene-expression at post-transcriptional level. Unlike other RNA species, blood miRNAs circulate in a highly stable form, either within extracellular vesicles or bound to proteins. In recent years, circulatory miRNA profiles have been proposed as potential biomarkers for multitude of pathologies, including essential hypertension. However, the evidence of miRNA biomarker potential is limited, mainly due to the scarcity of profiling studies associating miRNA levels with hypertension. Furthermore, most of these studies have been performed with preselected miRNA pool, limiting their discovery potential. Here, we summarize the results of the unbiased profiling studies and additionally discuss findings from targeted miRNA analysis. Only miR-30e has been found to be associated with hypertension in more than one unbiased study. The targeted analyses highlight the association of miR-1, -21, -34a, -92a, -122, -126, -143, -145, -605, -623, -1299, as well as let-7 and miR-30 families with hypertension. Current literature indicates that some of these miRNAs are involved in hypertension-associated vascular dysfunction and the development of atherosclerosis, suggesting a novel mechanism for cardiovascular disease risk posed by hypertension. All in all, studies associating hypertension with circulatory miRNA profiles are scarce, with several limitations affecting the comparability of the studies. This review discusses the functions and potential mechanisms linking the identified miRNAs to hypertension and underscores the need for further research.

The 2024 Nobel Prize in Physiology or Medicine has been awarded to two pioneering researchers, Victor Ambros and Gary Ruvkun, marking the fourth time research using Caenorhabditis elegans (C. elegans) has received this prestigious recognition. With a rapid life cycle of just 3.5 days and four distinct larval stages, C. elegans serves as an ideal model for exploring complex genetic mechanisms, particularly heterochronic gene regulation. Ambros and Ruvkun's groundbreaking work on lin-4 and lin-14 genes in C. elegans revealed that lin-4 functions as a 22-nucleotide small RNA-now known as a microRNA (miRNA)-that binds complementarily to the 3' UTR of lin-14 mRNA, effectively inhibiting LIN-14 protein synthesis. This discovery was the first demonstration of miRNA in post-transcriptional gene regulation, a finding that has since reshaped our understanding of genetic regulation across species. Their research on small RNAs in C. elegans not only opened a new paradigm in molecular biology but also highlighted the power of this model organism in uncovering universal biological principles.

An ethanolic extract of Corylus avellana L. hazelnut was characterised by liquid chromatography coupled to high resolution mass spectrometry. We here evaluated the in vitro cytotoxic response to such extract in HepG2 cells and tried to depict the underlying mechanism(s) in terms of microRNA-34b/c involvement. Following long-term exposure (144h) of HepG2 cells with 0.04-0.4 mg/ml of hazelnut extract, we demonstrated that miR-34 precursor RNA and both mature miR-34b and miR-34c molecules underwent a significant stimulation (>2-fold change, p < 0.05) in cells treated with the highest concentration. The epigenetic modulation was accompanied by the inhibition of cell proliferation, the decrease of viability and activation of apoptosis at 144h of treatment with 0.4 mg/ml of hazelnut.These in vitro findings demonstrate the cytotoxic effect of the C. avellana extract in HepG2 cells and open the way to in vivo validation of possible application of hazelnut-based extracts, and/or its metabolites, as promising epigenetics drugs.

microRNAs (miRNAs) are small non-coding RNAs regulating gene expression. They have attracted significant interest as biomarkers for early diagnosis, prediction and monitoring of treatment response in many diseases. As individual miRNAs often lack the required sensitivity and specificity, miRNA signatures are developed for clinical applications. Digital PCR (dPCR) is a sensitive fluorescent-based quantification method, that can be used to detect the expression of miRNAs in patient samples. Our study presents the first proof-of-concept of a multiplexed dPCR assay for the simultaneous analysis and quantification of multiple miRNAs.

After reverse transcription (RT) using a pool of miRNA-specific stem-loop primers, dPCR was performed with a universal reverse primer and miRNA-specific forward primers along with fluorescently-labelled hydrolysis probes. Multiple experimental parameters were evaluated and strategies for modulating the observed signals were devised. The optimised assay was applied to the analysis of miRNAs from cell lines and biological samples. Although absolute quantification was lost, due to the reverse transcription step, quantification was linear for the dilution series and results were highly reproducible for independent dPCR and RT reactions. Our results confirmed the high sensitivity of dPCR for patient samples.

We demonstrate the feasibility and reliability of multiplexed detection and quantification of miRNAs by dPCR that can be applied in a clinical setting to evaluate miRNA signatures.

Patients with estrogen receptor-positive breast cancer undergoing continuous adjuvant hormone therapy often experience delayed recurrence with tamoxifen use, potentially causing adverse effects. However, the lack of biomarkers hampers patient selection for extended endocrine therapy. This study aimed to elucidate the molecular mechanisms underlying delayed recurrence and identify biomarkers. When miRNA expression was assessed in luminal breast cancer tissues with and without delayed recurrence using NanoString, a significant increase in the expression of miR483-3p was observed in samples from patients with delayed recurrence compared with those without. miR483-3p expression was elevated in tamoxifen resistant (TAMR) EFM19 cells than in non-resistant EFM19 cells. Notably, genes associated with cancer metastasis (AMOTL2, ANKRD1, CTGF, and VEGF) were upregulated in TAMR EFM19 cells, although cell motility and proliferation were reduced. Transfection of miR483-3p mimics into both non-resistant EFM19 and MCF7 cells resulted in increased expression of cancer metastasis-related genes, but decreased proliferation and migration. Given that miR483-3p can bind to the 3'UTR region of O-GlcNAc transferase (OGT) and potentially affect its protein expression, we examined OGT protein levels and found that transfection with miR483-3p mimics selectively reduced OGT expression. Overall, breast cancer cells subjected to long-term hormone therapy displayed elevated miR483-3p expression, reducing motility and dormancy induction via decreased OGT expression. These findings suggest that miR483-3p is a potential biomarker for long-term endocrine therapy.

Extrachromosomal circular DNA (eccDNA), a chromosome-independent circular DNA, has garnered significant attention due to its widespread distribution and intricate biogenesis in carcinoma. Existing research findings propose that multiple eccDNAs contribute to drug resistance in cancer treatments through complex and interrelated regulatory mechanisms. The unique structure and genetic properties of eccDNA increase tumor heterogeneity. This increased diversity is a result of eccDNA's ability to stimulate oncogene remodeling and participate in anomalous splicing processes through chimeric cyclization and the reintegration of loop DNA back into the linear genome. Such actions promote oncogene amplification and silencing. eccDNA orchestrates protein interactions and modulates protein degradation by acting as a regulatory messenger. Moreover, it plays a pivotal role in modeling the tumor microenvironment and intensifying the stemness characteristics of tumor cells. This review presented detailed information about the biogenesis, distinguishing features, and functions of eccDNA, emphasized the role and mechanisms of eccDNA during cancer treatment, and further proposed the great potential of eccDNA in inspiring novel strategies for precision cancer therapy and facilitating the discovery of prognostic biomarkers for cancer.

B lymphocytes (B cells) are a type of white blood cell that play an essential role in the adaptive immune response. They are derived from pluripotent hematopoietic stem cells and undergo several developmental stages in the bone marrow and secondary lymphoid organs to become effector cells. B cells can act as antigen-presenting cells, secrete cytokines, generate immunological memory as memory B cells, and produce and secrete high-affinity antibodies as plasma B cells.B-cell development occurs in discontinuous steps within specific organs and niche environments, progressing through checkpoints controlled by the relative levels of numerous transcription factors, cytokines, and surface receptors. These complex interactions of distinct developmental programs operate through balanced control mechanisms rather than simple "on/off" signals.Over the past two decades, much has been learned about short non-coding RNA (ncRNA) molecules that play a critical role in fine-tuning gene expression by targeting specific messenger RNAs (mRNAs) for degradation or translational repression. In the intricate orchestration of B-cell development, ncRNAs contribute to the delicate balance between proliferation, differentiation, and apoptosis by influencing key checkpoints in the maturation process.Therefore, in this chapter, I will review the role of different classes of small ncRNAs, including microRNAs, glycoRNAs, tRNA-derived fragments, and ribosomal RNA-derived fragments, in modulating gene expression at the post-transcriptional level and their contribution to the intricate regulatory network that controls B-cell maturation.

Osteosarcoma is one of the most common primary malignant bone tumours in children and adolescents, frequently arising from mesenchymal tissue in the distal femur. It is highly aggressive, often metastasising to the lungs. Current treatments, which include surgery combined with neoadjuvant chemotherapy and radiotherapy, are often unsatisfactory due to the inability of surgery to control metastasis and the side effects and drug resistance associated with chemotherapy. Thus, there is an urgent need for new treatment technologies. This study explored the use of nanoparticles for gene and drug delivery in osteosarcoma treatment. The nanoparticles were composed of biodegradable and biocompatible polymers, chitosan and PLGA, and were loaded with miRNA-34a, a short RNA molecule that functions as a tumour suppressor by inducing cell cycle arrest and apoptosis in osteosarcoma cells. Recognising that the co-delivery of multiple drugs can enhance treatment efficacy while reducing systemic toxicity and drug resistance, three additional classes of nanoparticles were developed by adding doxorubicin and resveratrol to the chitosan-PLGA-miRNA-34a core. A layer-by-layer technique was employed to create a bilayer nanocoating using pectin and chitosan as polyelectrolytes, for encapsulating the therapeutic payloads. The manufactured nanoparticles were tested on U2OS and Saos-2 cells to assess cell viability, metabolic activity, and morphology before and after treatment. Cells were treated in both two-dimensional cultures and three-dimensional osteosarcoma spheroids, creating a biomimetic cellular model. Increased apoptotic activity and disruption of cellular functions were primarily observed with nanoparticles co-delivering miRNA-34a and drugs, particularly those functionalised with the LbL nanocoating, as confirmed by PCR analysis.

Zebrafish (Danio rerio) are a good model for cancer research including studies on chemotherapy treatments. We treated wild-type and miR-34a deletion mutant zebrafish embryos at 24 h post-fertilization with 1 µM of the topoisomerase I inhibitor, camptothecin (CPT), for 4 h to catalogue gene expression changes induced by this DNA damage treatment and to understand if these changes are influenced by loss of miR-34a. The 4 sample groups of 3 independent biological samples consisting of 30 embryos each were analyzed by RNA-sequencing using the recently updated zebrafish transcriptome annotation based on GRCz11, which enabled a more complete and sensitive read mapping and gene assignment than standard annotations. Using this gene expression estimates dataset as the primary resource, we performed a differentially expressed gene (DEG) analysis based on treatment as loss of miR-34a had minimal effects on CPT-induced expression changes. The DEGs were analyzed for Gene Ontology and KEGG pathway terms. Enriched terms and pathways among up-regulated genes were mostly related to stress, cell death, cell cycle regulation, transcriptional regulation, cell signalling, developmental processes and synthesis of retinol and steroid hormones. By contrast, down-regulated genes were most strongly associated with genes involved in key developmental processes, adhesion molecules, as well as some transport and metabolic pathways, together suggesting a "developmental shutdown". We also identified interferon-regulated genes and p53 target genes activated or inhibited by DNA damage due to topoisomerase I inhibition, suggesting that they are important components of the response to this type of DNA damage in zebrafish embryos.

In chronic lymphocytic leukemia (CLL), TP53 mutations or deletions on chromosome 17p lead to adverse prognosis and reduced levels of miR-34a, which targets NOTCH1. Also, hyperactivated NOTCH1 signaling is crucial for CLL progression. Here we explored the interaction between p53, miR-34a, and NOTCH1 in CLL. We investigated the effect of p53 and miR-34a on NOTCH1 signaling and expression in CLL cells with altered TP53. Our results indicate that miR-34a reduces NOTCH1 3' UTR activity but might not be a mediator between p53 signaling and NOTCH1. p53 activation increases miR-34a expression and NOTCH1 protein levels, correlating with decreased NOTCH1 and miR-34a levels in primary CLL cells with TP53 alterations. Some samples with high NOTCH1 levels presented increased BCL-2, suggesting an anti-apoptotic mechanism of a potentially direct p53-NOTCH1 relation in CLL. This study deepens the understanding of the p53-miR-34a-NOTCH1 signaling network, providing insights that could guide future therapeutic strategies for CLL.

Sphingosine-1-phosphate receptor 1 (S1PR1) is considered to be closely related to a variety of malignant tumors, but the role and mechanism of S1PR1 in lung adenocarcinoma are not fully understood. In this study, we aim to explore the role and downstream signaling pathways of S1PR1 in the malignant biological functions of lung adenocarcinoma (LUAD).

Bioinformatics analysis, RT-qPCR, western blot and immunohistochemistry (IHC) were was used to investigate the expression of S1PR1 in LUAD. The prognosis of S1PR1 was also analyzed. CCK-8 assay, colony formation assay, scratch assay, transwell migration and invasion assay, cell adhesion assay were performed to examine the effect of S1PR1 on LUAD. RNA sequencing was employed to analyze the DEGs in LUAD cells overexpressing S1PR1. Enrichment pathway analysis using KEGG, GO, and GSEA was conducted to predict potential signaling pathways and downstream targets. chromatin immunoprecipitation (ChIP) and dual luciferase reporter assay were performed to verify the direct regulation between FOXA1 and the target genes. Then FOXA1 overexpression were performed to functional rescue experiments. miRNA-30c-5p was identified as a microRNA regulating FOXA1 by dual luciferase reporter assay. The downstream signaling pathways of S1PR1 was detected to clarify the specific pathways to regulates miR-30c-5p.

S1PR1 is significantly decreased in LUAD and is positively correlated with the prognosis. Overexpression of S1PR1 inhibits the proliferation, migration, invasion and adhesion function of LUAD cells by suppressing the expression of COL5A1, MMP1, and SERPINE1. FOXA1 is a key transcription factor regulating the expression of MMP1, COL5A1 and SERPINE1. S1PR1 inhibits the expression of FOXA1 through p-STAT1/miR-30c-5p, thereby suppressing the malignant function of LUAD cells.

The expression of S1PR1 is downregulated in LUAD, which is positively correlated with prognosis. S1PR1 regulates the malignant function of LUAD cells by inhibiting the expression of COL5A1, MMP1 and SERPINE1 through the p-STAT1/miR-30c-5p/FOXA1 signaling pathway.

One of the main health issues in the modern world is cancer, with breast cancer (BC) as one of the most common types of malignancies. Different environmental and genetic risk factors are involved in the development of BC. One of the primary genes implicated in cancer development is the p53 gene, which is also known as the "gatekeeper" gene. p53 is involved in cancer development by interacting with numerous pathways and signaling factors, including microRNAs (miRNAs). miRNAs are small noncoding RNA molecules that regulate gene expression by binding to the 3' untranslated region of target mRNAs, resulting in their translational inhibition or degradation. If the p53 gene is mutated or degraded, it can contribute to the risk of BC by disrupting the expression of miRNAs. Similarly, the disruption of miRNAs causes the negative regulation of p53. Therefore, the p53/miRNA axis is a crucial pathway in the progression or prevention of BC, and understanding the regulation and function of this pathway may contribute to the development of new therapeutic strategies to help treat BC.

The aim of this research was to elucidate the role of miR-34b in cervical cancer progression and the underlying mechanism behind the miR-34b-mediated tumor suppression. The study revealed the role of miR-34b as a senescence inducer and serves as a potential therapeutic target in developing combination therapy with senotherapeutics.

MiR-34b was ectopically expressed in cervical cancer cell lines using a tetracycline inducible system and its effects on cell viability, apoptosis, senescence, DNA damage and oxidative stress were studied using MTT assay, acridine orange/ ethidium bromide staining, senescence associated β-galactosidase assay, gamma H2AX foci staining assay, western blotting and specific dyes for the detection of total and individual ROS species.

Ectopic expression of miR-34b promoted cellular senescence but no significant induction of apoptosis was observed in cervical cancer cell lines. MiR-34b promoted increase in oxidative stress through increase in total and individual ROS species and contributed to increase in cellular senescence. Mechanistically, miR-34b mediates its action by targeting TWIST1 as evidenced by the similar actions of TWIST1 shRNA in cervical cancer cell lines. Furthermore, our study revealed TWIST1 is one of the most significant targets of miR-34b targetome and identified RITA as a novel senolytic agent for use in combination therapy with miR-34b.

MiR-34b promotes cellular senescence and oxidative stress by targeting TWIST1, a known oncogene and EMT regulator. This study delved into the mechanism of miR-34b-mediated tumor suppression and provided novel insights for development of miR-34b based therapeutics for cervical cancer.

Renal fibrosis is a major cause of renal dysfunction and is a common pathological event in almost all forms of chronic kidney disease (CKD). Currently, the pathomechanisms of renal fibrosis are not well understood. However, researchers have demonstrated that aerobic exercise can improve renal fibrosis. Klotho is considered to be a negative regulator of renal fibrosis. In this study, we aimed to investigate the role and mechanism of Klotho in the improvement of renal fibrosis through aerobic exercise. We performed a 12-week aerobic exercise intervention in 19-month-old male C57BL/6J mice. Physiological and biochemical indexes were performed to assess renal function and renal fibrosis. The roles of Klotho were further confirmed through knockdown of Klotho by small interfering RNA (siRNA) in C57BL/6J mice.Q-PCR and Western blot were performed to quantify determine the expression of relevant genes and proteins in the kidney. Results: Aging decreased Klotho expression via activated the upstream TGF-β1/p53/miR34a signaling pathway and affected its downstream signaling pathways, ultimately leading to renal fibrosis. Exposure to aerobic exercise for 12 weeks significantly improved renal fibrosis and alleviated the intrarenal genetic alterations induced by aging. Conclusion: Our results showed that aerobic exercise increased Klotho expression by inhibiting the TGF-β1/p53/miR34a signaling pathway and further inhibited its downstream TGF-β1/smad3 and β-linker protein signaling pathways. These results provide a theoretical basis supporting the feasibility of exercise in the prevention and treatment of CKD.

Highly conformal delivery of radiation therapy (RT) has revolutionized the treatment landscape for primary and metastatic liver cancers, yet concerns persist regarding radiation-induced liver disease (RILD). Despite advancements, RILD remains a major dose-limiting factor due to the potential damage to normal liver tissues by therapeutic radiation. The toxicity to normal liver tissues is associated with a multitude of physiological and pathological consequences. RILD unfolds as multifaceted processes, intricately linking various responses, such as DNA damage, oxidative stress, inflammation, cellular senescence, fibrosis, and immune reactions, through multiple signaling pathways. The DNA damage caused by ionizing radiation (IR) is a major contributor to the pathogenesis of RILD. Moreover, current treatment options for RILD are limited, with no established biomarker for early detection. RILD diagnosis often occurs at advanced stages, highlighting the critical need for early biomarkers to adjust treatment strategies and prevent liver failure. This review provides an outline of the diverse molecular and cellular mechanisms responsible for the development of RILD and points out all of the available biomarkers for early detection with the aim of helping clinicians decide on advance treatment strategies from a single literature recourse.

Glioblastoma (GBM), a grade IV brain tumor, presents a severe challenge in treatment and eradication due to its high genetic variability and the existence of stem-like cells with self-renewal potential. Conventional therapies fall short of preventing recurrence and fail to extend the median survival of patients significantly. However, the emergence of gene therapy, which has recently obtained significant clinical outcomes, brings hope. It has the potential to be a suitable strategy for the treatment of GBM. Notably, microRNAs (miRNAs) have been noticed as critical players in the development and progress of GBM. The combined usage of hsa-miR-34a and Cytosine Deaminase (CD) suicide gene and 5-fluorocytosine (5FC) prodrug caused cytotoxicity against U87MG Glioma cells in vitro. The apoptosis and cell cycle arrest rates were measured by flow cytometry. The lentiviral vector generated overexpression of CD/miR-34a in the presence of 5FC significantly promoted apoptosis and caused cell cycle arrest in U87MG cells. The expression level of the BCL2, SOX2, and P53 genes, target genes of hsa-miR-34a, was examined by quantitative real-time PCR. The treatment led to a substantial downregulation of Bcl2 and SOX2 genes while elevating the expression levels of Caspase7 and P53 genes compared to the scrambled control. The hsa-miR-34a hindered the proliferation of GBM cancer cells and elevated apoptosis through the P53-miR-34a-Bcl2 axis. The CD suicide gene with 5FC treatment demonstrated similar results to miR-34a in the apoptosis, cell cycle, and real-time assays. The combination of CD and miR-34a produced a synergistic effect. In vivo, anti-GBM efficacy evaluation in rats bearing intracranial C6 Glioma cells revealed a remarkable induction of apoptosis and a significant inhibition of tumor growth compared with the scrambled control. The simultaneous use of CD/miR-34a with 5FC almost entirely suppressed tumor growth in rat models. The combined application of hsa-miR-34a and CD suicide gene against GBM tumors led to significant induction of apoptosis in U87MG cells and a considerable reduction in tumor growth in vivo.

Aneuploidy is a hallmark of human cancer, yet the molecular mechanisms to cope with aneuploidy-induced cellular stresses remain largely unknown. Here, we induce chromosome mis-segregation in non-transformed RPE1-hTERT cells and derive multiple stable clones with various degrees of aneuploidy. We perform a systematic genomic, transcriptomic and proteomic profiling of 6 isogenic clones, using whole-exome DNA, mRNA and miRNA sequencing, as well as proteomics. Concomitantly, we functionally interrogate their cellular vulnerabilities, using genome-wide CRISPR/Cas9 and large-scale drug screens. Aneuploid clones activate the DNA damage response and are more resistant to further DNA damage induction. Aneuploid cells also exhibit elevated RAF/MEK/ERK pathway activity and are more sensitive to clinically-relevant drugs targeting this pathway, and in particular to CRAF inhibition. Importantly, CRAF and MEK inhibition sensitize aneuploid cells to DNA damage-inducing chemotherapies and to PARP inhibitors. We validate these results in human cancer cell lines. Moreover, resistance of cancer patients to olaparib is associated with high levels of RAF/MEK/ERK signaling, specifically in highly-aneuploid tumors. Overall, our study provides a comprehensive resource for genetically-matched karyotypically-stable cells of various aneuploidy states, and reveals a therapeutically-relevant cellular dependency of aneuploid cells.

MiRNAs are a class of non-coding RNAs acting as gene expression regulators by modulating the lifespan of messenger RNA. Commonly referred to as the most frequent leukemia in the Western world, chronic lymphocytic leukemia (CLL) is a lymphoproliferative malignancy characterized by clonal expansion of CD19, CD23, and CD5-positive mature B-cells. While this pathology is regarded as less aggressive and has a variety of treatment options, the cause of its clinical heterogeneity is not yet understood. Moreover, the prognostic markers and treatment recommendations based on predictive markers are limited. This review aims to investigate some miRNAs that are dysregulated and possibly involved in CLL pathogenesis as a starting point for the proposal of new prognostic and predictive markers and, as more agents targeting miRNA expression become available, their potential role as therapeutic targets.

During pseudoglandular stage of the human lung development the primitive bronchial buds are initially conformed by simple tubules lined by endoderm-derived epithelium surrounded by mesenchyme, which will progressively branch into airways and start to form distal epithelial saculles. For first time alveolar type II (AT2) pneumocytes appears. This study aims to characterize the genes and microRNAs involved in this differentiation process and decipher its role in the starting alveolar differentiation.

Gene and microRNA profiling was performed in human embryonic lungs from 7 to 12 post conception weeks (pcw). Protein expression location of candidate genes were analyzed by immunofluorescense in embryonic lung tissue sections. mRNA/miRNA target pairs were identified using computational approaches and their expression was studied in purified epithelial/mesenchymal cell populations and in isolated tips and stalks from the bronchial tree. Additionally, silencing experiments in human embryonic lung mesenchymal cells and in human embryonic tip-derived lung organoids were performed, as well as organoid differentiation studies. AT2 cell markers were studied by qRT-PCR and by immunofluorescence. The TGFB-β phosphorylated pathways was analyzed with membrane protein arrays. Lung explants were cultured in air/liquid interface with/without peptides.

We identified 88 differentially expressed genes, including IGFBP3. Although IGFBP3 mRNA was detected in both epithelial and mesenchymal populations, the protein was restricted to the epithelium, indicating post-transcriptional regulation preventing IGFBP3 protein expression in the mesenchyme. MicroRNA profiling identified miR-34a as an IGFBP3 regulator. miR-34a was up-regulated in mesenchymal cells, and its silencing in human embryonic lung mesenchymal cells increased IGFBP3 levels. Additionally, IGFBP3 expression showed a marked downregulation from 7 to 12 pcw, suggesting its involvement in the differentiation process. The differentiation of human tip-derived lung embryonic organoids showed a drastic reduction in IGFBP3, supported by the scRNAseq data. IGFBP3 silencing in organoids activated an alveolar-like differentiation process characterized by stem cell markers downregulation and upregulation of AT2 markers. This process was mediated by TGFβ signalling inhibition and BMP pathway activation.

The IGFBP3/miR-34a axis restricts IGFBP3 expression in the embryonic undifferentiated lung epithelium, and the progressive downregulation of IGFBP3 during the pseudoglandular stage is required for alveolar differentiation.

The mud crab (Scylla paramamosain) is a commercially significant marine decapod crustacean. Due to its obvious sexual dimorphism, the mechanism of sex differentiation and gonadal development has attracted significant research interest. The Dmrt (double-sex and mab-3 related transcription factor) genes are vital in animal gonadal development and sex differentiation. In the present study, miR-34 was predicted to target the 3' end of Dmrt-1, idmrt-2, Dmrt-3, Dsx and Dmrt-like genes by prediction software, and the interactions between miR-34 and these Dmrt genes were validated by in vivo and in vitro experiments. Dual luciferase assay results indicated that miR-34 mimics/inhibitors co-transfected with plasmid vectors with 3' end of Dmrt-1, idmrt-2, Dmrt-3, Dsx and Dmrt-like, respectively, led to a significant decrease/increase of fluorescence activity in HEK293T cells. In vivo experiments showed that injection of agomir-34 significantly inhibited Dmrt-1, idmrt-2, Dsx and Dmrt-like expression, while injection of antagomir-34 caused the opposite result. However, Dmrt-3 expression was not affected by injection of miR-34 reagents. Meanwhile, the expression of spermatogenesis and testicular development-related molecular marker genes (IAG, foxl2 and vasa) in mud crabs was significantly changed after injecting the miR-34 reagent in vivo. Furthermore, the result of immunoblotting proved that the expression level of Dmrt-like protein can be regulated by miR-34. These results imply that miR-34 is indirectly involved in sex differentiation and testicular development of S. paramamosain by regulating Dmrt-1, idmrt-2, Dsx and Dmrt-like genes.

Within the follicular fluid, extracellular vesicles (EVs) guide oocyte growth through their cargo microRNAs (miRNAs). Here, we investigated the role of EVs and their cargo miRNAs by linking the miRNAs found in EVs, derived from the fluid of an individual follicle, to the ability of its oocyte to become a blastocyst (competent) or not (non-competent).

Bovine antral follicles were dissected, categorized as small (2-4 mm) or large (5-8 mm) and the corresponding oocytes were subjected to individual maturation, fertilization and embryo culture to the blastocyst stage. Follicular fluid was pooled in 4 groups (4 replicates) based on follicle size and competence of the corresponding oocyte to produce a blastocyst. Follicular fluid-derived EVs were isolated, characterized, and subjected to miRNA-sequencing (Illumina Miseq) to assess differential expression (DE) in the 4 groups. Functional validation of the effect of miR-34c on embryo development was performed by supplementation of mimics and inhibitors during in vitro maturation (IVM).

We identified 16 DE miRNAs linked to oocyte competence when follicular size was not considered. Within the large and small follicles, 46 DE miRNAs were driving blastocyst formation in each group. Comparison of EVs from competent small and large follicles revealed 90 DE miRNAs. Cell regulation, cell differentiation, cell cycle, and metabolic process regulation were the most enriched pathways targeted by the DE miRNAs from competent oocytes. We identified bta-miR-34c as the most abundant in follicular fluid containing competent oocytes. Supplementation of miR-34c mimic and inhibitor during IVM did not affect embryo development. However, blastocyst quality, as evidenced by higher cell numbers, was significantly improved following oocyte IVM in the presence of miR-34c mimics, while miR-34c inhibitors resulted in the opposite effect.

This study demonstrates the regulatory effect of miRNAs from follicular fluid-derived EVs on oocyte competence acquisition, providing a further basis for understanding the significance of miRNAs in oocyte maturation and embryonic development. Up-regulation of miR-34c in EVs from follicular fluid containing competent oocytes and the positive impact of miR-34c mimics added during IVM on the resulting blastocysts indicate its pivotal role in oocyte competence.

This study aims to explore novel microRNAs in urine for screening and predicting clinical characteristics in pancreatic cancer (PC) patients using a microRNA array-based approach.

We used the Toray® 3D-Gene microRNA array-based approach to compare urinary levels between PC patients and healthy volunteers.

(1) Four oncogenic microRNAs (miR-744-5p, miR-572, miR-210-3p, and miR-575) that were highly upregulated in the urine of PC patients compared to healthy individuals were identified by comprehensive microRNA array analysis. (2) Test-scale analysis by quantitative RT-PCR for each group of 20 cases showed that miR-210-3p was significantly upregulated in the urine of PC patients compared to healthy individuals (P = 0.009). (3) Validation analysis (58 PC patients and 35 healthy individuals) confirmed that miR-210-3p was significantly upregulated in the urine of PC patients compared to healthy individuals (P < 0.001, area under the receiver operating characteristic curve = 0.79, sensitivity: 0.828, specificity: 0.743). We differentiated PC patients into invasive ductal carcinoma (IDCa) and intraductal papillary mucinous carcinoma (IPMC) groups. In addition to urinary miR-210-3p levels being upregulated in IDCa over healthy individuals (P = 0.009), urinary miR-210-3p levels were also elevated in IPMC over healthy individuals (P = 0.0018). Urinary miR-210-3p can differentiate IPMC from healthy individuals by a cutoff of 8.02 with an AUC value of 0.762, sensitivity of 94%, and specificity of 63%. (4) To test whether urinary miR210-3p levels reflected plasma miR-210-3p levels, we examined the correlation between urinary and plasma levels. Spearman's correlation analysis showed a moderate positive correlation (ρ = 0.64, P = 0.005) between miR-210-3p expression in plasma and urine.

Urinary miR-210-3p is a promising, non-invasive diagnostic biomarker of PC, including IPMC.

Not applicable.

The three most common kinds of urologic malignancies are prostate, bladder, and kidney cancer, which typically cause substantial morbidity and mortality. Early detection and effective treatment are essential due to their high fatality rates. As a result, there is an urgent need for innovative research to improve the clinical management of patients with urologic cancers. A type of small noncoding RNAs of 22 nucleotides, microRNAs (miRNAs) are well-known for their important roles in a variety of developmental processes. Among these, microRNA-21 (miR-21) stands out as a commonly studied miRNA with implications in tumorigenesis and cancer development, particularly in urological tumors. Recent research has shed light on the dysregulation of miR-21 in urological tumors, offering insights into its potential as a prognostic, diagnostic, and therapeutic tool. This review delves into the pathogenesis of miR-21 in prostate, bladder, and renal cancers, its utility as a cancer biomarker, and the therapeutic possibilities of targeting miR-21.

The aging process is linked to numerous cellular changes, among which are modifications in the functionality of dermal fibroblasts. These fibroblasts play a crucial role in sustaining the healing of skin wounds. Reduced cell proliferation is a hallmark feature of aged dermal fibroblasts. Long intergenic non-coding RNA (lincRNAs), such as LincRNA-EPS (Erythroid ProSurvival), has been implicated in various cellular processes. However, its role in aged dermal fibroblasts and its impact on the cell cycle and its regulator, Cyclin D1 (CCND1), remains unclear. Primary dermal fibroblasts were isolated from the skin of 17-week-old (young) and 88-week-old (aged) mice. Overexpression of LincRNA-EPS was achieved through plasmid transfection. Cell proliferation was detected using the MTT assay. Real-time PCR was used to quantify relative gene expressions. Our findings indicate a noteworthy decline in the expression of LincRNA-EPS in aged dermal fibroblasts, accompanied by reduced levels of CCND1 and diminished cell proliferation in these aging cells. Significantly, the overexpression of LincRNA-EPS in aged dermal fibroblasts resulted in an upregulation of CCND1 expression and a substantial increase in cell proliferation. Mechanistically, LincRNA-EPS induces CCND1 expression by sequestering miR-34a, which was dysregulated in aged dermal fibroblasts, and directly targeting CCND1. These outcomes underscore the crucial role of LincRNA-EPS in regulating CCND1 and promoting cell proliferation in aged dermal fibroblasts. Our study provides novel insights into the molecular mechanisms underlying age-related changes in dermal fibroblasts and their implications for skin wound healing. The significant reduction in LincRNA-EPS expression in aged dermal fibroblasts and its ability to induce CCND1 expression and enhance cell proliferation highlight its potential as a therapeutic target for addressing age-related skin wound healing.

Lung cancer is the deadliest cancer type worldwide with ~ 1.8 million deaths per-year. Smoking accounts for ~ 85% of all cases, with a described joint effect with unhealthy diet in lung cancer risk increase. Public health policies to prevent carcinogens exposure, promote smoking cessation and advocacy for healthy nutrition, are therefore highly recommended. Here we have examined the benefits of the Mediterranean Diet (MedDiet) in protecting against some non-communicable diseases including lung cancer, highlighting the epidemiological and biomolecular aspects of MedDiet anti-inflammatory effect and its interaction with smoking habits closely linked to risk of lung cancer. Considering the high incidence and mortality rates of lung cancer, we discussed also about the global impact that a Planeterranean extension of the benefits of MedDiet could have on controlling lung cancer risk. We also debated the impact of personalized nutrition on lung cancer prevention, considering individual heterogeneity in response to diet plans as well as recent advancements on nutri-omics in lung cancer research, with a specific focus on the role of microRNAs (miRNAs) as a promising nutritional molecular hub for lung cancer prevention. We strongly believe that a deep understanding of the molecular link between food components and genetic/epigenetics factors can expand effective intervention strategies.

Prostate cancer is one of the most common malignancies among men worldwide. Besides genetic alterations, epigenetic modulations including DNA methylation, histone modifications and miRNA mediated alteration of gene expression are the key driving forces for the prostate tumor development and cancer progression. Aberrant expression and/or the activity of the epigenetic modifiers/enzymes, results in aberrant expression of genes involved in DNA repair, cell cycle regulation, cell adhesion, apoptosis, autophagy, tumor suppression and hormone response and thereby disease progression. Altered epigenome is associated with prostate cancer recurrence, progression, aggressiveness and transition from androgen-dependent to androgen-independent phenotype. These epigenetic modifications are reversible and various compounds/drugs targeting the epigenetic enzymes have been developed that are effective in cancer treatment. This chapter focuses on the epigenetic alterations in prostate cancer initiation and progression, listing different epigenetic biomarkers for diagnosis and prognosis of the disease and their potential as therapeutic targets. This chapter also summarizes different epigenetic drugs approved for prostate cancer therapy and the drugs available for clinical trials.

Bladder cancer (BC) is a highly frequent neoplasm in correlation with significant rate of morbidity, mortality, and cost. The onset of BC is predominantly triggered by environmental and/or occupational exposures to carcinogens, such as tobacco. There are two distinct pathways by which BC can be developed, including non-muscle-invasive papillary tumors (NMIBC) and non-papillary (or solid) muscle-invasive tumors (MIBC). The Cancer Genome Atlas project has further recognized key genetic drivers of MIBC along with its subtypes with particular properties and therapeutic responses; nonetheless, NMIBC is the predominant BC presentation among the suffering individuals. Radical cystoprostatectomy, radiotherapy, and chemotherapy have been verified to be the common therapeutic interventions in metastatic tumors, among which chemotherapeutics are more conventionally utilized. Although multiple chemo drugs have been broadly administered for BC treatment, cisplatin is reportedly the most effective chemo drug against the corresponding malignancy. Notwithstanding, tumor recurrence is usually occurred following the consumption of cisplatin regimens, particularly due to the progression of chemo-resistant trait. In this framework, non-coding RNAs (ncRNAs), as abundant RNA transcripts arise from the human genome, are introduced to serve as crucial contributors to tumor expansion and cisplatin chemo-resistance in bladder neoplasm. In the current review, we first investigated the best-known ncRNAs, i.e. microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), correlated with cisplatin chemo-resistance in BC cells and tissues. We noticed that these ncRNAs could mediate the BC-related cisplatin-resistant phenotype through diverse cellular processes and signaling mechanisms, reviewed here. Eventually, diagnostic and prognostic potential of ncRNAs, as well as their therapeutic capabilities were highlighted in regard to BC management.

During aging, regenerative tissues must dynamically balance the two opposing processes of proliferation and cell death. While many microRNAs are differentially expressed during aging, their roles as dynamic regulators of tissue regeneration have yet to be described. We show that in the highly regenerative Drosophila testis, miR-34 levels are significantly elevated during aging. miR-34 modulates germ cell death and protects the progenitor germ cells from accelerated aging. However, miR-34 is not expressed in the progenitors themselves but rather in neighboring cyst cells that kill the progenitors. Transcriptomics followed by functional analysis revealed that during aging, miR-34 modifies integrin signaling by limiting the levels of the heterodimeric integrin receptor αPS2 and βPS subunits. In addition, we found that in cyst cells, this heterodimer is essential for inducing phagoptosis and degradation of the progenitor germ cells. Together, these data suggest that the miR-34-integrin signaling axis acts as a sensor of progenitor germ cell death to extend progenitor functionality during aging.

microRNAs (miRNAs) are a class of small non-coding RNAs that play a crucial regulatory role in fundamental biological processes and have been implicated in various diseases, including cancer. The first evidence of the cancer-related function of miRNAs was discovered in chronic lymphocytic leukemia (CLL) in the early 2000s. Alterations in miRNA expression have since been shown to strongly influence the clinical course, prognosis, and response to treatment in patients with CLL. Therefore, the identification of specific miRNA alterations not only enhances our understanding of the molecular mechanisms underlying CLL but also holds promise for the development of novel diagnostic and therapeutic strategies. This review aims to provide a comprehensive summary of the current knowledge and recent insights into miRNA dysregulation in CLL, emphasizing its pivotal roles in disease progression, including the development of the lethal Richter syndrome, and to provide an update on the latest translational research in this field.

The exogenous delivery of miRNA to mimic and restore miRNA-34a activity in various cancer models holds significant promise in cancer treatment. Nevertheless, its effectiveness is often impeded by challenges, including a short half-life, propensity for off-target accumulation, susceptibility to inactivation by blood-based enzymes, concerns regarding patient safety, and the substantial cost associated with scaling up. As a means of overcoming these barriers, we propose the development of miRNA-loaded Tat-A86 nanoparticles by virtue of Tat-A86's ability to shield the loaded agent from external environmental factors, reducing degradation and inactivation, while enhancing circulation time and targeted accumulation.

Genetically engineered Tat-A86, featuring 16 copies of the interleukin-4 receptor (IL-4R)-binding peptide (AP1), Tat for tumor penetration, and an elastin-like polypeptide (ELP) for presenting target ligands and ensuring stability, served as the basis for this delivery system. Comparative groups, including Tat-E60 and A86, were employed to discern differences in binding and penetration. The designed ELP-based nanoparticle Tat-A86 effectively condensed miRNA, forming stable nanocomplexes under physiological conditions. The miRNA/Tat-A86 formulation bound specifically to tumor cells and facilitated stable miRNA delivery into them, effectively inhibiting tumor growth. The efficacy of miRNA/Tat-A86 was further evaluated using three-dimensional spheroids of lewis lung carcinoma (LLC) as in vitro model and LLC tumor-bearing mice as an in vivo model. It was found that miRNA/Tat-A86 facilitates effective cell killing by markedly improving miRNA penetration, leading to a substantial reduction in the size of LLC spheroids. Compared to other controls, Tat-A86 demonstrated superior efficacy in suppressing the growth of 3D cellular aggregates. Moreover, at equivalent doses, miRNA-34a delivered by Tat-A86 inhibited the growth of LLC cells in allograft mice.

Overall, these studies demonstrate that Tat-A86 nanoparticles can deliver miRNA systemically, overcoming the basic hurdles impeding miRNA delivery by facilitating both miRNA uptake and stability, ultimately leading to improved therapeutic effects.

Parental experiences can affect the phenotypic plasticity of offspring. In locusts, the population density that adults experience regulates the number and hatching synchrony of their eggs, contributing to locust outbreaks. However, the pathway of signal transmission from parents to offspring remains unclear. Here, we find that transcription factor Forkhead box protein N1 (FOXN1) responds to high population density and activates the polypyrimidine tract-binding protein 1 (Ptbp1) in locusts. FOXN1-PTBP1 serves as an upstream regulator of miR-276, a miRNA to control egg-hatching synchrony. PTBP1 boosts the nucleo-cytoplasmic transport of pre-miR-276 in a "CU motif"-dependent manner, by collaborating with the primary exportin protein exportin 5 (XPO5). Enhanced nuclear export of pre-miR-276 elevates miR-276 expression in terminal oocytes, where FOXN1 activates Ptbp1 and leads to egg-hatching synchrony in response to high population density. Additionally, PTBP1-prompted nuclear export of pre-miR-276 is conserved in insects, implying a ubiquitous mechanism to mediate transgenerational effects.