Search Results (8,409)

Dicer, a cytoplasmic type III RNase, is essential for the maturation of microRNAs (miRNAs) and is implicated in cancer progression and chemoresistance. Our previous research demonstrated that phosphorylation of Dicer at S1016 alters miRNA maturation and glutamine metabolism, contributing to gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). In this study, we focused on the role of Dicer phosphorylation at S1728/S1852 in GEM-resistant PDAC cells. Using shRNA to knock down Dicer in GEM-resistant PANC-1 (PANC-1 GR) cells, we examined cell viability through MTT and clonogenic assays. We also expressed phosphomimetic Dicer 2E (S1728E/S1852E) and phosphomutant Dicer 2A (S1728A/S1852A) to evaluate their effects on GEM resistance and metabolism. Our results show that phosphorylation at S1728/S1852 promotes GEM resistance by reprogramming glutamine metabolism. Specifically, phosphomimetic Dicer 2E increased intracellular glutamine, driving pyrimidine synthesis and raising dCTP levels, which compete with gemcitabine’s metabolites. This metabolic shift enhanced drug resistance. In contrast, phosphomutant Dicer 2A reduced GEM resistance. These findings highlight the importance of Dicer phosphorylation in regulating metabolism and drug sensitivity, offering insights into potential therapeutic strategies for overcoming GEM resistance in pancreatic cancer. Full article

Targeted treatment of tuberculosis-associated lung damage requires an understanding of the precise mechanisms of immunopathology. A major obstacle to the longitudinal study of tuberculosis (TB) immunopathogenesis in humans is the lack of serial lung biopsies during disease progression and treatment, which could be used to characterize local immune pathways involved in tissue damage. Understanding of the immunobiology of lung tissue damage in tuberculosis has largely been based on animal models. Our study looked for signs of inflammation in TB patients’ lung biopsies. Results were compared between a site of infection and relatively healthy tissue outside the site. The most significant differences in the expression of microRNAs (miRs) and cytokine/chemokines were observed between the non-decayed tuberculoma and the surrounding parenchyma. In addition, these parameters showed almost no differences between the cavitary wall and surrounding tissue. This is an indication that the inflammatory process is more prevalent in fibrotic cavitary tuberculosis (FCT). In FCT subjects, no difference was observed between the cavity wall and the parenchyma in the production of key inflammatory factors such as IL-6, IL-11, IL-17, and IFNγ. This is an indication that the limits of the inflammatory response are broader in FCT. The expression levels of miR-191, miR-193a, miR-222, miR-223, miR-18, miR-155, miR-376c, miR-26a, miR-150, and miR-124 were not significantly different between the cavernous wall and lung tissue in patients with FCT, further confirming the spread of inflammatory and destructive processes beyond the focus of infection. Full article

Ischemic stroke is a leading cause of disability and mortality worldwide. Recently, increasing evidence implicates microRNAs (miRs) in the pathophysiology of ischemic stroke. Studies have shown that miR-15a/16-1 is abnormally expressed in brains after ischemic stroke, and its upregulation may increase ischemic damage. Given that sex and age are significant modifiers of stroke outcomes, here we investigated whether inhibiting miR-15a/16-1 with antagomirs mitigates cerebral ischemia/reperfusion (I/R) injury in a sex- and age-dependent manner. Young (3 months) and aged (18 months) male and female C57/BL mice underwent 1-h middle cerebral artery occlusion and 3–7 days reperfusion (tMCAO). We administered miR-15a/16-1 antagomir (30 pmol/g) or control antagomir (NC, 30 pmol/g) via tail vein 2 h post-MCAO. Neurobehavioral testing and infarct volume assessment were performed on days 3 and 7. Compared to controls, antagomir treatment significantly improved neurobehavioral outcomes and reduced infarct volume in tMCAO mice at day 7, with the effects being more pronounced in young mice. Notably, young female mice exhibited superior survival and sensorimotor function compared to young male mice. These results were also replicated in a permanent MCAO (pMCAO) mice model. This suggests miR-15a/16-1 antagomir and estradiol may synergistically regulate genes involved in neurovascular cell death, inflammation, and oxidative stress, with sex and age-dependent expression of miR-15a/16-1 and its targets likely underlying the observed variations. Overall, our findings identify miR-15a/16-1 antagomir as a promising therapeutic for ischemic stroke and suggest that sex and age should be considered when developing miR-based therapeutic strategies. Full article

To assay new circulating markers related to macrovascular complications (MVC) in type 2 diabetes mellitus (T2DM), we carried out a descriptive cross-sectional study. We recruited 30 controls (CG), 34 patients with T2DM (DG), and 28 patients with T2DM and vascular complications (DG+C); among them, 22 presented MVC. Peripheral blood was used to determine redox status (superoxide dismutase, SOD; catalase, CAT; glutathione reductase, GRd; glutathione peroxidase, GPx; glucose-6-phosphate dehydrogenase, G6PD) and markers of oxidative damage (advanced oxidation protein products, AOPP; lipid peroxidation, LPO), nitrite levels in plasma (NOx). Inflammatory markers (IL-1β, IL-6, IL-10, IL-18, MCP-1, TNF-α) and the relative expression of c-miRNAs were analyzed. The real-time PCR results showed that the expressions of miR-155-5p, miR-21-5p, miR-146a-3p, and miR-210-3p were significantly higher in the DG group compared to the CG. The DG+C group presented statistically relevant differences with CG for four miRs: the increased expression of miR-484-5p, miR-21-5p, and miR-210-3p, and decreased expression of miR-126a-3p. Moreover, miR-126a-3p was significantly less expressed in DG+C compared to DG. The application of binary logistic regression analysis and construction of receiving operator characteristic curves (ROC) revealed two models with high predictive values for vascular complications presence: (1) HbAc1, creatinine, total cholesterol (TC), LPO, GPx, SOD, miR-126, miR-484 (Exp(B) = 0.926, chi² = 34.093, p < 0.001; AUC = 0.913). (2) HbAc1, creatinine, TC, IL-6, LPO, miR-126, miR-484 (Exp(B) = 0.958, Chi² = 33.863, p < 0.001; AUC = 0.938). Moreover, our data demonstrated that gender, TC, GPx, CAT, and miR-484 were associated with MVC and exhibited higher predictive values (Exp(B) = 0.528, p = 0.024, Chi² = 28.214, AUC = 0.904) than classical variables (Exp(B) 0.462, p = 0.007, Chi² = 18.814, AUC = 0.850). miR-126, miR-484, IL-6, SOD, CAT, and GPx participate in vascular damage development in the studied diabetic population and should be considered for future studies. Full article

For research on HIV/AIDS, it is important to elucidate the complex viral–host interaction, host dependency factors (HDFs), and restriction factors. However, the regulatory network of HIV-resistance-related factors remains not well understood. Therefore, we integrated four publicly available HIV-related transcriptome datasets, along with three datasets on HIV-infection-related DNA methylation, miRNA, and ChIP-seq, to predict the factors influencing HIV resistance and infection. Our approach involved differential analysis, functional annotation, and protein–protein interaction network analysis. Through comprehensive analyses, we identified 25 potential HIV-resistance-related genes (including shared EGF) and 24 HIV-infection-related hub genes (including shared JUN). Additionally, we pinpointed five key differentially methylated genes, five crucial differentially expressed microRNAs, and five significant pathways associated with HIV resistance. We mapped the potential regulatory pathways involving these HIV-resistance-related factors. Among the predicted factors, RHOA, RAD51, GATA1, IRF4, and CXCL8 have been validated as HDFs or restriction factors. The identified factors, such as JUN, EGF, and PLEK, are potential HDFs or restriction factors. This study uncovers the gene signatures and regulatory networks associated with HIV-1 resistance, suggesting potential targets for the development of new therapies against HIV/AIDS. Full article

Fluorescent biosensor, which has the characteristics of high sensitivity, specificity, and low cost, can be directly detected in physiological fluids such as blood and serum. Therefore, the development of fluorescence sensor platforms for miRNA detection has a positive effect on the prevention and treatment of various diseases. In this paper, miR-34a was selected as a biological indicator of Alzheimer’s disease (AD). We designed a circular single-stranded DNA (CSSD) biosensor, which uses two unmodified single-stranded DNA (ssDNA) with complementary ends, DNAa and DNAb, to form CSSD by DNA sequence pairing to improve thermal stability and achieve signal amplification. At the same time, CSSD can react with miR-34a, and then the DNA of the DNA–RNA chain is hydrolyzed by duplex-specific nuclease (DSN enzyme). Finally, miR-34a is released to partake in the subsequent step, thus realizing cycle amplification. By evaluating the change in fluorescence signal under the optimized conditions, we discovered that this approach exhibits impressive sensitivity, with a detection threshold reaching as low as 0.36 nM. This surpasses the performance of numerous preceding miRNA detection biosensors. Furthermore, the system displays excellent detection capabilities even in intricate settings like serum, showcasing a strong ability to differentiate and choose effectively. In summary, this is a signal-off fluorescent biosensor, which realizes the purpose of double amplification of biosensor signal by using CSSD and enzyme assistance so that it can be used as a valuable tool for early diagnosis of diseases. Full article

Somatic embryogenesis is valuable for clonal propagation and genetic improvement, and it also serves as an ideal system for studying plant development mechanisms. In Larix kaempferi, microRNA171 and its target gene L. kaempferi SCARECROW-LIKE6 (LaSCL6), which has two alternative splicing variants, can regulate somatic embryogenesis; however, the underlying molecular mechanism is still unknown. In this study, we overexpressed these two LaSCL6 variants in Oryza sativa and Arabidopsis thaliana and then used the RNA-Seq method to screen genes from O. sativa and A. thaliana, whose expression patterns are related to those of LaSCL6 variants. The screened genes were then used to search L. kaempferi proteins to identify the candidate target genes of LaSCL6. After yeast one-hybrid and dual- luciferase transcriptional activity assays, cytochrome P450, family 89, subfamily A, polypeptide 5 (CYP89A5), and wall-associated receptor kinase-like 20 (WAKL20) were confirmed to be the target genes of LaSCL6-var1; in addition, WAKL20 and UDP-glycosyltransferase 85A3 (UGT85A3) were confirmed to be the target genes of LaSCL6-var2. Moreover, APETALA2-like protein 2, a transcription factor from the AP2/ERF family, was shown to interact with LaSCL6-var1 and LaSCL6-var2. Taken together, our results suggest a regulatory network of miR171-LaSCL6. The findings presented here not only provide novel insights into the regulation of the miR171-LaSCL6 module but also explain the mechanism underlying larch somatic embryogenesis and other biological processes. Full article

The nematode Dirofilaria immitis is responsible for a vector-borne disease affecting canines and humans worldwide, known as cardiopulmonary dirofilariasis. An accurate and early diagnosis is of the utmost importance for effective disease management. While traditional microscopy-based methods remain invaluable, they have inherent limitations. Serological tests, in particular ELISA and immunochromatographic tests, are employed due to their capacity to detect D. immitis antigens, offering ease of use and diagnostic accuracy. The advent of molecular methods has the potential to enhance routine diagnostic approaches, with polymerase chain reaction (PCR) and real-time PCR (qPCR) becoming the most prevalent techniques. Despite not yet being integrated into routine diagnostics, which are predominantly based on the Knott’s test and serological methods, these techniques offer significant benefits in the context of scientific research. This article proceeds to examine the potential of advanced techniques, such as high-resolution melting qPCR (HRM-qPCR), loop-mediated isothermal amplification (LAMP), droplet digital PCR (ddPCR), and microRNA (miRNA) detection, which are capable of enhanced sensitivity and early detection. The following work provides an in-depth analysis of the various diagnostic methods, emphasising the necessity of the continuous improvement and adaptation of these tools to effectively combat D. immitis. The findings underscore the importance of integrating these advanced methods into routine practice to improve detection rates and outcomes for infected animals. Full article

Background: Exercise is an essential pillar for human health, as it contributes to physical, mental, and emotional well-being. Well-recognized international organizations, such as the World Health Organization, advocate for integrating exercise into healthy lifestyles, recognizing its importance in disease prevention and improving quality of life. However, despite the consensus on its value, there is no universal agreement on specific prescriptions for vulnerable groups, highlighting the need for personalized approaches that consider the unique characteristics and needs of everyone. Emerging studies have demonstrated that exercise training performed at the intensity that elicits maximal fat oxidation improves insulin sensitivity, cardiorespiratory fitness, and body composition in patients with obesity, making it a highly effective strategy for long-term weight management and metabolic health in this specific population. Methods: The present study protocol settles the basis for a 16-week randomized clinical trial based on exercise prescription at the maximal fat oxidation rate combined with resistance training in young individuals with overweight and obesity. Expected Results: This study will elucidate how FatMax, with or without resistance exercises, can enhance metabolic flexibility, increase fat oxidation, and improve body composition, evaluating changes in biochemical parameters (cholesterol, glucose, triglycerides, and inflammatory markers), metabolic biomarkers (determination of fat and carbohydrate utilization rates during rest and exercise), and epigenetic indicators (focusing on microRNAs associated with adipogenesis, inflammation, and fat metabolism). ClinicalTrials.gov identification number: NCT06553482 (FatMax Training on Metabolic and Epigenetic Parameters). Full article

Background: miRNAs are short, non-coding RNAs whose deregulation has been shown in painful processes, including musculoskeletal pain. This condition, which causes disability, impacts quality of life, and contributes to substantial healthcare costs, is also a critical issue in sports. In this case-control study, we evaluated the expression of four miRNAs involved in inflammation in runners with musculoskeletal pain and elucidated their functions and pathophysiological implications. Methods: A total of 17 runners with musculoskeletal pain and 17 age- and sex-matched runners without pain participated in this study. The levels of the miRNAs were evaluated by qRT-PCR. Bioinformatic tools were employed to identify the target genes and biological processes regulated by these miRNAs. Results: Compared to the controls, the runners with musculoskeletal pain exhibited significantly higher plasma levels of miR-133b (p = 0.02), miR-155-5p (p = 0.003) and let-7a-5p (p = 0.02). Multivariable regression analysis indicated that these three miRNAs exhibit a positive correlation (p < 0.05) with the presence of musculoskeletal pain, adjusted for age. Bioinformatic analysis suggested that the miRNAs hub genes are involved in regulatory processes, neuroinflammatory pathways, and human diseases that are associated with pain pathology. Conclusions: These results enhance our understanding of the potential role of miR-133b, miR-155-5p and let-7a-5p in pain-associated biological processes. The miRNA-mediated negative regulation of genes identified could explain the inflammatory and tissue repair processes in this population. Further studies are needed to confirm and validate the role of these miRNAs in painful conditions, especially considering the significant public health implications of managing inflammatory pain in sports. Full article

Reactive oxygen species (ROS) are intermediates in oxidation–reduction reactions with the capacity to modify biomolecules and temporarily or permanently alter cell behaviour through signalling pathways under physiological and pathophysiological conditions where there is an imbalance between oxidative factors and the antioxidant response of the organism, a phenomenon known as oxidative stress. Evidence suggests that the differential modulation of ROS-mediated oxidative stress occurs in the pathogenesis and progression of melanoma, and that this imbalance in redox homeostasis appears to be functionally linked to microRNA (miRNA o miRs)-mediated non-mutational epigenetic reprogramming involving genes and transcription factors. The relationship between ROS-mediated stress control, tumour microenvironment, and miRNA expression in melanoma is not fully understood. The aim of this review is to analyse the involvement of miRNAs in the modulation of the signalling pathways involved in ROS-mediated oxidative stress in melanoma. It is hoped that these considerations will contribute to the understanding of the mechanisms associated with a potential epigenetic network regulation, where the modulation of oxidative stress is consolidated as a common factor in melanoma, and therefore, a potential footprint poorly documented. Full article

Bamboo plants have erratic flowering habits with a long vegetative growth and an uncertain flowering cycle. The process of floral transition has always been one of the hot and intriguing topics in bamboo developmental biology. As master modulators of gene expression at the post-transcriptional level, miRNAs play a crucial role in regulating reproductive growth, especially in floral transition of flowering plants. Pleioblastus pygmaeus is a kind of excellent ground cover ornamental bamboo species. In this study, we performed miRNA expression profiling of the shoot buds and flower buds from the bamboo species, to investigate flowering-related miRNAs in bamboo plants. A total of 179 mature miRNAs were identified from P. pygmaeus, including 120 known miRNAs and 59 novel miRNAs, of which 96 (61 known miRNAs and 35 novel miRNAs) were differentially expressed in the shoots at different growth stages. Based on target gene (TG) prediction, a total of 2099 transcription factors (TFs) were annotated to be TGs of the 96 differentially expressed miRNAs (DEMs), corresponding to 839 recordings of DEM-TF pairs. In addition, we identified 23 known DEMs involved in flowering and six known miRNAs related to floral organ development based on previous reports. Among these, there were 11 significantly differentially expressed miRNAs, with 124 TF targets corresponding to 132 DEM-TF pairs in P. pygmaeus. In particular, we focused on the identification of miR156a-SPL (SQUAMOSA Promoter-Binding protein-Like) modules in the age pathway, which are well-known to regulate the vegetative-to-reproductive phase transition in flowering plants. A total of 36 TF targets of miR156a were identified, among which there were 11 SPLs. The Dual-Luciferase transient expression assay indicated miR156a mediated the repression of the PpSPL targets in P. pygmaeus. The integrated analysis of miRNAs and TGs at genome scale in this study provides insight into the essential roles of individual miRNAs in modulating flowering transition through regulating TF targets in bamboo plants. Full article

Micro RNAs (miRNA) are a type of non-coding RNA involved in gene regulation and can be associated with diseases such as cancer, cardiovascular, and neurological diseases. As such, identifying the entire genome of miRNA can be of great relevance. Since experimental methods for novel precursor miRNA (pre-miRNA) detection are complex and expensive, computational detection using Machine Learning (ML) could be useful. Existing ML methods are often complex black boxes that do not create an interpretable structural description of pre-miRNA. In this paper, we propose a novel framework that makes use of generative modeling through Variational Auto-Encoders to uncover the generative factors of pre-miRNA. After training the VAE, the pre-miRNA description is developed using a decision tree on the lower dimensional latent space. Applying the framework to miRNA classification, we obtain a high reconstruction and classification performance while also developing an accurate miRNA description. Full article

Background/Objectives: Male infertility is a complex condition with various underlying genetic factors. microRNAs (miRNAs) play a crucial role in gene regulation, and their disruption can significantly impact fertility. This study aimed to identify variants within miRNA genes and elucidate their impact on male infertility. Methods: Whole genome sequencing was performed on blood samples from men with asthenozoospermia, oligozoospermia, and teratozoospermia, compared to normozoospermic controls. The analysis revealed a significant number of unique variants in each infertile group. We subsequently focused on variants in miRNA regions, followed by an in silico analysis to investigate the role of the identified variants and miRNAs in male infertility. Results: Focused analysis on miRNA genes identified 19 exclusive variants in teratozoospermic men, 24 in asthenozoospermic, and 27 in oligozoospermic, all mapping to pre-miRNAs or mature miRNAs. Functional analyses using Gene Ontology (GO) and KEGG pathways highlighted key biological processes and pathways disrupted by these variants and miRNA–mRNA interactions, including transcription regulation, signaling, and cancer-related pathways. Furthermore, six variants (rs17797090, rs1844035, rs7210937, rs451887, rs12233076, and rs6787734) were common across the infertile groups, suggesting their importance in male infertility or their potential as biomarkers. Common variants were also validated in another clinically relevant group of men. Some miRNAs with identified variants, such as hsa-miR-449b and hsa-miR-296, have been previously implicated in male infertility and exhibit differential expression between fertile and infertile men, according to the literature, too. Conclusion: These results provide new insights into the genetic basis of male infertility and open avenues for future research and therapeutic interventions. Full article

Background/Objectives: The prognosis of colorectal cancer (CRC) is mainly based on the clinical stage; however, CRC is considered a complex disease due to its molecular heterogeneity. The development of novel biomarkers to improve patients’ diagnosis and prognosis remains fundamental. Methods: A cohort of forty-nine CRC patients from the National Cancer Institute of Mexico was included to collect clinical and miRNA expression data. The expression of a group of miRNAs was compared between CRC and non-tumoral adjacent tissues. Prognosis assessment considering each miRNA expression was tested using Kaplan–Meier survival curves and Cox regressions. Statistical significance was defined as p ≤ 0.05. Trial registration: Retrospective study No.2021/046. Results: miR-3065-5p and miR-26a-5p expression differed between non-tumoral adjacent and tumoral tissues (p = 0.02). In terms of overall survival (OS), patients with low expression of miR-3065-5p had a median OS of 70 months, while patients with high levels did not reach the median OS (p = 0.041). Male patients with low expression of this miRNA had an OS of 70 months, whereas patients with high levels did not reach the median OS (p = 0.050). Under uni-multivariate analysis, clinical stage (HR: 1.30, CI 1.23–2.30; p: 0.001) and low levels of miR-3065-5p (HR: 1.30, CI 1.23–2.30; p: 0.001) were determined as predictor factors of OS. To this end, we designed the “Prognosis miRNAs assessment in cancer” (PROMIR-C) algorithm, which integrated clinical features with miR-3065-5p expression levels. Conclusions: These findings support the clinical utility of miR-26a-5p and miR-3065-5p in the diagnosis and prognosis of CRC. PROMIR-C is a fundamental tool for clinicians in treatment decision-making, prognosis assessment, and outcome of CRC. Full article