Search Results (3,635)

Background: Cardiomyocyte death is a key factor in myocardial ischemia–reperfusion injury (MI/RI), and the expression patterns and molecular mechanisms of pyroptosis-related genes (PRGs) in ischemia–reperfusion injury are poorly understood. Methods: The mouse MI/RI injury-related datasets GSE61592 and GSE160516 were obtained from the Gene Expression Omnibus database, and differential expression analysis was performed on each to identify differentially expressed genes (DEGs). The DEGs were intersected with the PRGs obtained from GeneCards to identify differentially expressed PRGs in MI/RI. Enrichment analysis identified key pathways, while PPI network analysis revealed hub genes. The expression patterns and immune cell infiltration of hub genes were also investigated. The molecular docking prediction of key genes was performed using MOE software in conjunction with the ZINC small molecular compounds database. Key gene expression was validated in an external dataset (GSE4105), a mouse MI/RI model, and an HL-1 cell hypoxia/reoxygenation model via RT-qPCR. Results: A total of 29 differentially expressed PRGs were identified, which are primarily associated with pathways such as “immune system process”, “response to stress”, “identical protein binding”, and “extracellular region”. Seven key genes (Fkbp10, Apoe, Col1a2, Ppic, Tlr2, Fstl1, Serpinh1) were screened, all strongly correlated with immune infiltration. Seven FDA-approved small molecule compounds exhibiting the highest docking potential with each key gene were selected based on a comprehensive evaluation of S-scores and hydrogen bond binding energies. Apoe, Tlr2, and Serpinh1 were successfully validated across external datasets, the mouse MI/RI model, and the cardiomyocyte H/R model. Conclusions: Apoe, Tlr2, and Serpinh1 may be key genes involved in MI/RI-related pyroptosis. Targeting these genes may provide new insights into the treatment of MI/RI. Full article

Fibrotic diseases of the skin and lung, such as systemic sclerosis, hypertrophic scars, keloids, and pulmonary fibrosis, share core molecular mechanisms despite their distinct anatomical settings. Central to their pathogenesis are persistent fibroblast activation, immune dysregulation, ECM remodeling, and failure of resolution pathways, all modulated by an ever-changing environment and epigenetic regulation. Increasing evidence reveals that chronic injury from air pollution, ultraviolet radiation, climate stressors, and occupational hazards accelerates fibroinflammatory remodeling across these barrier organs. Moreover, shared signaling networks, including TGF-β, IL-4/IL-13, Wnt/β-catenin, and epigenetic regulators like miR-21 and miR-29, suggest convergent fibrotic programs may be subject to cross-organ therapeutic targeting. This review integrates recent insights into the exposome’s role in driving fibrosis, highlights novel RNA- and epigenetic-based interventions, and evaluates the repurposing of antifibrotic agents approved for pulmonary disease within dermatologic contexts. We emphasize the emerging concept of fibrosis-aware precision medicine and propose a unifying framework to guide integrated therapeutic strategies. In the face of global climate change and rising environmental insults, a cross-organ perspective on fibrosis offers a timely and translationally relevant approach to addressing this growing burden on human health. Full article

Sulfate availability critically influences plant growth, yet the role of small RNAs, particularly microRNAs (miRNAs), in regulating responses to sulfate deficiency remains poorly understood. Here, we conducted a temporal analysis of sulfate deficiency-responsive miRNAs in the roots and leaves of Solanum lycopersicum (tomato), using an updated miRNA annotation in the SL4.0 genome. We found 40 differentially expressed miRNAs, including 2 novel, tomato-specific miRNAs. Tomato miRNAs showed an important time- and organ-specific regulation, similar to the described response of the mRNA transcriptome. Integration with transcriptomic data and Degradome-seq analysis highlighted both canonical and non-canonical targets for sulfate-responsive miRNAs. miR395, the most extensively studied miRNA, was found to control not only its conserved targets involved in sulfate transport and assimilation, but also genes involved in redox homeostasis, photosynthesis and chloride transport. Notably, most targets were repressed in leaves, suggesting miRNA-mediated downregulation of energy-intensive processes, while root targets were predominantly upregulated, including genes related to protein remodeling and antioxidant defense. Comparative analysis with Arabidopsis thaliana revealed a broader functional repertoire in tomato, suggesting species-specific adaptations to sulfate deficiency. Overall, our results underscore the critical role of miRNAs in fine-tuning organ-specific metabolic reprogramming during nutrient stress, expanding the current understanding of the regulatory landscape underlying sulfate deficiency in plants. Full article

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and the third leading cause of cancer-related death. Hyperactivation of oncogenes and suppression of tumor suppressor genes/proteins drive HCC initiation and progression. MicroRNAs (miRNAs) critically modulate HCC biology by regulating proliferation, apoptosis, and metastasis. Acting either as tumor suppressors or oncomiRs, they shape core signaling pathways, including PI3K/Akt/mTOR, Hippo–YAP/TAZ, Wnt/β-catenin, RAS/MAPK, and p53. Their dysregulation in tissues and body fluids renders them promising diagnostic biomarkers and therapeutic targets. Preclinical studies demonstrate that miRNA-based strategies—either restoring tumor-suppressive miRNAs (e.g., miR-34a, miR-125a-5p) or inhibiting oncogenic miRNAs (e.g., miR-660-5p)—can suppress HCC progression and reduce treatment resistance. Combination approaches, such as pairing miR-122 mimics with miR-221 inhibitors or delivering miR-326 via nanoparticles, further enhance efficacy by simultaneously targeting multiple oncogenic pathways. This review summarizes recent advances in miRNA-mediated regulation of HCC signaling and highlights their clinical potential, including ongoing trials of miRNA-based diagnostics and therapeutics for early detection, prognostication, and personalized treatment. Full article

MicroRNAs (miRNAs) are well known for regulating translation in the cytoplasm, yet their nuclear roles remain poorly understood. Previously, we identified spliceosome-associated miRNAs implicated in tumorigenesis and metastasis in breast cancer models. Here, we investigate their nuclear functions in the immortalized human cortical neuron (HCN) cell line, along with glioblastoma (U87MG) and neuroblastoma (SH-SY5Y) cell lines, both widely used as models for brain cancer research. Our findings reveal that spliceosome-associated miRNAs mark neuronal cancer cells and uncover novel nuclear targets. Notably, some spliceosomal miRNAs exhibit opposing regulatory effects in the nucleus compared to the cytoplasm, while others demonstrate potential novel nuclear functions. A prominent example is miR-99b, which overlaps the 5′ splice junction of the poorly characterized long non-coding RNA (lncRNA) sperm acrosome-associated 6 antisense RNA1 (SPACA6-AS1) and, through base pairing, enhances SPACA6-AS1 pre-mRNA levels. These results highlight the diverse and context-dependent functions of nuclear miRNAs in gene regulation and cancer progression, broadening our understanding of their regulatory potential beyond the cytoplasm. Full article

Objective: Insulin resistance (IR) is a complex and multifactorial disorder that contributes to type 2 diabetes and cardiovascular disease. MicroRNAs (miRNAs) play important roles in diverse developmental and disease processes. However, the molecular mechanisms of IR are unclear. This paper aims to explore the role of miRNA in regulating IR and to elucidate the mechanisms responsible for these effects. Methods: IR models were created by feeding a high-fat diet (HFD) to mice or stimulating 3T3-L1 cells with palmitate. Twelve weeks of HFD trigger weight gain, leading to lipid accumulation and insulin resistance in mice. The expression profiles of miRNAs in adipose tissues (AT) from the HFD-induced mouse models were analyzed. The relationship between miR-221-3p and SOCS1 was determined using dual luciferase reporter gene assays. Metabolic alterations in AT were investigated by real-time PCR and Western blot. Results: miR-221-3p was significantly increased in AT. HFD-induced disturbances in glucose homeostasis were aggravated by miR-221-3p upregulation. The inhibition of miR-221-3p promoted insulin sensitivity including reduced lipid accumulation and the disruption of glucose metabolism. Of note, the 3′-UTR of SOCS1 was found to be a direct target of miR-221-3p. The SOCS1 inhibitor attenuated miR-221-3p-induced increases in IRS-1 phosphorylation, AKT phosphorylation, and GLUT4. miR-221-3p was considered to be involved in the PI3K/AKT signaling pathway, thus leading to increased insulin sensitivity and decreased IR in HFD-fed mice and 3T3-L1 adipocytes. Conclusions: The miR-221-3p/SOCS1 axis in AT plays a pivotal role in the regulation of glucose metabolism, providing a novel target for treating IR and diabetes. Full article

Cancer stem cells (CSCs), a subpopulation of tumor cells endowed with self-renewal capacity, drive cancer initiation and progression. While long non-coding RNAs (lncRNAs) are increasingly recognized as critical regulators of CSC stemness, their specific roles in gastric cancer stem cells (GCSCs) remain poorly understood. This study investigates the functional significance of lncRNA TSPEAR-AS2 in modulating GCSC properties and uncovers its underlying molecular mechanisms. Through integrated whole-transcriptome sequencing, bioinformatics analysis, and validation in 48 paired gastric cancer tissues and adjacent normal tissues, TSPEAR-AS2 was identified as a differentially expressed lncRNA upregulated in both GCSCs and tumor samples. Functional experiments revealed that TSPEAR-AS2 overexpression significantly enhanced GCSC sphere-forming ability, proliferation, cell cycle progression, epithelial–mesenchymal transition (EMT), and expression of stemness markers (CD54, CD44, OCT4, NANOG, and SOX2) while suppressing apoptosis. Conversely, TSPEAR-AS2 knockdown attenuated these malignant phenotypes. In vivo tumorigenicity assays in nude mice further confirmed that TSPEAR-AS2 promotes tumor growth, with overexpression accelerating and knockdown inhibiting tumor formation. Mechanistically, bioinformatics predictions and dual-luciferase reporter assays established TSPEAR-AS2 as a competing endogenous RNA (ceRNA) that sponges miR-15a-5p, thereby derepressing the miR-15a-5p target gene CCND1. Rescue experiments demonstrated that overexpression of miR-15a-5p phenocopied TSPEAR-AS2 knockdown, reducing GCSC stemness, while miR-15a-5p inhibition rescued the effects of TSPEAR-AS2 suppression. Collectively, these findings reveal a novel TSPEAR-AS2/miR-15a-5p/CCND1 regulatory axis that sustains GCSC stemness and tumorigenicity. These results highlight TSPEAR-AS2 as a potential therapeutic target for eradicating gastric cancer stem cells and improving clinical outcomes. Full article

Background/Objectives: Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of abnormal plasma cells in bone marrow, predominantly affecting individuals over 65 years of age. Despite recent therapeutic advances, MM remains largely incurable due to frequent relapses and the emergence of drug resistance. MicroRNAs have emerged as key post-transcriptional regulators implicated in cancer progression, with miR-429 exhibiting context-dependent oncogenic or tumor-suppressive roles in various cancers. However, its function in MM has not been thoroughly investigated. Methods: miR-429 expression was evaluated in MM cells and patient samples by qRT-PCR. Functional effects were assessed through inhibition studies, proliferation/apoptosis assays, and co-culture with stromal cells. Results: In this study, we found that miR-429 expression is significantly downregulated in MM cell lines and primary malignant plasma cells compared to normal plasma cells. The functional inhibition of miR-429 in U266 cells led to a significant increase in cell proliferation without affecting spontaneous apoptosis, as confirmed in both MM cell lines and patient-derived plasma cells. Additionally, the inhibition of miR-429 in HS-5 stromal cells enhanced the proliferation of co-cultured MM cells, highlighting the role of the bone marrow microenvironment in disease progression. Conclusions: These findings suggest that miR-429 may act as a tumor suppressor by modulating MM cell proliferation. Although preliminary, our results support the need for further investigation into miR-429 as a potential biomarker or therapeutic target. Full article

Background: Despite clinical and pathological risk tools, predicting outcomes in non-muscle-invasive bladder cancer (NMIBC), particularly high-grade (HG) cases, remains challenging due to its unpredictable recurrence and progression. There is an urgent need for molecular biomarkers to enhance risk stratification and guide treatment. Methods: We assessed the prognostic potential of eight miRNAs (miR-9, miR-143, miR-182, miR-205, miR-27a, miR-369, let-7c, and let-7g) in a cohort of ninety patients with primary bladder cancer. Expression data were retrieved from our previously published studies. Kaplan–Meier’s and Cox’s regression analyses were used to evaluate the associations with overall survival (OS), metastasis-free survival (MFS), and clinical outcomes. Principal component analysis (PCA) was performed to identify informative miRNA combinations. Target gene prediction, pathway enrichment (DAVID), and drug–gene interaction mapping (DGIdb) were conducted in silico. Results: A high expression of let-7g and miR-9 was significantly associated with better OS in HG NMIBC and MIBC, respectively (p = 0.013 and p = 0.000). MiR-9 downregulation correlated with metastasis in MIBC (p = 0.018). Among all combinations, miR-205 and miR-27a best predicted intermediate-risk NMIBC progression and recurrence (r² = 0.982, p = 0.000). A functional analysis revealed that these miRNAs regulate key cancer-related pathways (MAPK, mTOR, and p53) through genes such as TP53, PTEN, and CDKN1A. Drug interaction mapping identified nine target genes (e.g., DAPK1, ATR, and MTR) associated with eight FDA-approved bladder cancer therapies, including cisplatin and gemcitabine. Conclusions: Let-7g, miR-9, miR-143, miR-182, and miR-205 emerged as promising biomarkers for outcome prediction in NMIBC. Their integration into liquid biopsy platforms could support non-invasive monitoring and personalized treatment strategies. These findings warrant validation in larger, prospective studies and through functional assays. Full article

Background: Freeze tolerance is an uncommon but highly effective strategy that allows certain vertebrates to survive prolonged exposure to subzero temperatures in a frozen, ischemic state. While past studies have characterized the metabolic and biochemical adaptations involved, including cryoprotectant accumulation and metabolic rate suppression, the contribution of post-transcriptional gene regulation by microRNAs (miRNAs) remains largely unexplored. This study investigated freeze-responsive miRNAs in cardiac tissue of the gray tree frog, Dryophytes versicolor, to better understand the molecular mechanisms that support ischemic survival and tissue preservation. Methods: Adult frogs were subjected to controlled freezing at −2.5 °C, and cardiac tissue was collected from frozen and control animals. Total RNA was extracted and analyzed via small RNA sequencing to identify differentially expressed miRNAs, followed by target gene prediction and KEGG pathway enrichment analysis. Results: A total of 3 miRNAs were differentially expressed during freezing, with significant upregulation of miR-93-5p and let-7b-5p and downregulation of miR-4485-3p. Predicted targets of upregulated miRNAs included genes involved in immune signaling pathways (e.g., cytokine–cytokine receptor interaction), steroid hormone biosynthesis, and neuroactive ligand–receptor interaction, suggesting suppression of energetically costly signaling processes. Downregulation of miRNAs targeting cell cycle, insulin signaling, and WNT pathways indicates possible selective preservation of cytoprotective and repair functions. Conclusion: Overall, these results suggest that D. versicolor employs miRNA-mediated regulatory networks to support metabolic suppression, maintain essential signaling, and prevent damage during prolonged cardiac arrest. This work expands our understanding of freeze tolerance at the molecular level and may offer insights into biomedical strategies for cryopreservation and ischemia–reperfusion injury. Full article

Alzheimer’s disease (AD) and major depressive disorder (MDD) are prevalent central nervous system (CNS) disorders that share overlapping symptoms but differ in underlying molecular mechanisms. Distinguishing these mechanisms is essential for developing targeted diagnostic and therapeutic strategies. In this study, we integrated multi-tissue transcriptomic datasets from brain and peripheral samples to identify differentially expressed microRNAs (miRNAs) in AD and MDD. Functional enrichment analyses (KEGG, GO) revealed that dysregulated miRNAs in AD were associated with MAPK, PI3K–Akt, Ras, and PD-1/PD-L1 signaling, pathways linked to synaptic plasticity, neuroinflammation, and immune regulation. In contrast, MDD-associated miRNAs showed enrichment in Hippo signaling and ubiquitin-mediated proteolysis, implicating altered neurogenesis and protein homeostasis. Network analysis highlighted key disease- and tissue-specific miRNAs, notably hsa-miR-1202 and hsa-miR-24-3p, with potential roles in neuronal survival and molecular network regulation. These findings suggest that miRNAs may serve as non-invasive biomarkers for diagnosis, prognosis, and treatment monitoring in both disorders. While therapeutic targeting of miRNAs offers promise, challenges such as blood–brain barrier penetration and tissue-specific delivery remain. This integrative approach provides a translational framework for advancing miRNA-based strategies in CNS disease research. Full article

Intrauterine growth restriction (IUGR) severely hinders the development of the livestock industry and impacts economic efficiency. MicroRNAs (miRNAs) participate in the epigenetic regulation of animal growth and development. Using IUGR pigs as a model, this study analyzed transcriptomic data from IUGR piglets to investigate the miRNA-mRNA regulatory network in their testes. Compared with NBW pigs, IUGR pigs exhibited reduced testicular volume, decreased weight, and abnormal testicular development. A total of 4945 differentially expressed mRNAs and 53 differentially expressed miRNAs were identified in IUGR testicular tissues, including 1748 downregulated and 3197 upregulated mRNAs, as well as 41 upregulated and 12 downregulated miRNAs. The integrated analysis of differentially expressed genes, miRNA target genes, and the miRNA-mRNA network revealed that IUGR may impair testicular development by disrupting cell cycle progression and apoptotic pathways, thereby hindering normal testicular cell growth. Furthermore, analysis of the miRNA-mRNA network indicated that miRNAs such as ssc-miR-23a, ssc-miR-29c, ssc-miR-193a-3p, and ssc-miR-574-3p could serve as potential marker miRNAs for IUGR testes, while YWHAZ, YWHAB, and PPP2CA may function as core target genes within this regulatory network. In conclusion, this study enhances our understanding of male reproduction in IUGR pigs and provides a theoretical foundation for preventing and treating IUGR-induced male reproductive disorders. Full article

Metabolically healthy (MHO) and unhealthy obesity (MUO) exhibit distinct molecular genetic mechanisms underlying metabolic disorders. Studying gene and microRNA expression in subcutaneous adipose tissue (SAT) may reveal key pathogenetic differences between these phenotypes. We compared the expression of genes (ADIPOQ, HIF1A, CCL2) and microRNAs (miR-142-3p, miR-155, miR-378) in SAT between MHO and MUO patients and assessed their association with metabolic parameters. The study included 39 obese patients (19 MHO, 20 MUO) and 10 healthy controls. SAT biopsies were analyzed using real-time PCR. Correlations with clinical and metabolic markers were evaluated. Obese patients showed decreased ADIPOQ (p = 0.039) and miR-142 (p = 0.008) expression and increased CCL2 (p = 0.004), miR-155 (p = 0.017), and miR-378 (p = 0.04) expression compared to the controls. MUO patients exhibited higher HIF1A expression (p = 0.03) and strong correlations between CCL2 and dyslipidemia (total cholesterol, triglycerides)/dysglycemia (fasting glucose) (r = 0.45, p = 0.03; r = 0.52, p = 0.01; r = 0.63, p = 0.001, respectively). miR-142 negatively correlated with fibrosis markers, while miR-378 was linked to insulin resistance. The differential gene and microRNA expression highlights the role of inflammation, hypoxia, and fibrosis in MUO pathogenesis. miR-142-3p, miR-155, and miR-378 may serve as potential biomarkers for metabolic risk stratification and therapeutic targets. Full article

The miR156 family, crucial for phase transition and stress responses in plants, remains functionally uncharacterized in the ecologically and commercially important gymnosperm Larix kaempferi. This study systematically investigated L. kaempferi miR156 through phylogenetic analysis, structural prediction, expression profiling during somatic embryogenesis, and heterologous functional validation in Arabidopsis. Four MIR156 family members (LkMIR156s) were identified in Larix kaempferi, each with a characteristic stem-loop structure and highly conserved mature sequences. Computational predictions indicated that these LkMIR156s target four LkSPL family genes (LkSPL1, LkSPL2, LkSPL3, and LkSPL9). qRT-PCR analysis showed that mature LkmiR156s expression remained relatively low during early embryonic development but was significantly upregulated at the cotyledonary stage (21–42 days). Precursor transcript levels peaked earlier (around 28 days) than those of the mature LkmiR156, which remained highly expressed throughout cotyledonary embryo development. This sustained high expression coincided with cotyledon morphogenesis and embryonic dormancy. Functional validation via heterologous overexpression of LkMIR156b1 in Arabidopsis resulted in increased rosette leaf numbers (42.86% ± 6.19%) and individual leaf area (54.90% ± 6.86%), phenotypically consistent with the established role of miR156 in growth regulation. This study reveals the temporal expression dynamics of LkmiR156s during L. kaempferi somatic embryogenesis and its coordinated expression patterns with cotyledon development and embryonic dormancy. The functional conservation of the miR156-SPL module was confirmed in a model plant, providing key molecular insights into the developmental regulatory network of conifers. These findings offer potential strategies for optimizing somatic embryogenesis techniques in conifer species. Full article

Type 2 diabetes mellitus (T2DM) is known to increase the risk of fragility fractures; however, the underlying mechanism is still elusive. Reduced miR-155 and elevated RHOA are known to drive bone resorption, but their role in T2DM remains unclear. This study investigates bone remodeling imbalances in T2DM through miR-155 and RHOA expression profiling. Three-month-old female Wistar rats were fed a high-calorie diet for 3 weeks, followed by intraperitoneal injections of two lower doses of streptozotocin at weekly intervals to induce T2DM. Bone analysis from diabetic rats tested using qRT-PCR showed significantly reduced miR-155 levels and elevated RHOA. Histological analysis showed a 12.65% increase in Tb.Sp, 10.07% decrease in Tb.Th, and significant increase (p < 0.05) in apoptotic osteocytes. The bone turnover marker CTx-1 level was increased by 20.84%, and RANKL levels were significantly increased in T2DM. IL-1β and TNF-α were increased in T2DM. Bone resorption is more likely to occur in T2DM as both IL-1β and TNF-α work synergistically to promote osteoclastogenesis. MiR-155 could be an important modulator of bone remodeling in T2DM and a potential therapeutic target for diabetic osteopathy. Full article