Search Results (253)

Background: Breast cancer (BC) is highly heterogeneous, with varying molecular characteristics, such as reliance on autophagy. Autophagy is a critical cellular degradation process that helps cells survive under stress, but its regulation can be influenced by altered microRNA (miRNA) expression. Studying miRNA changes during starvation-induced autophagy in both mammary epithelial cells and BC cells could reveal potential molecular therapy targets. Methods: Rat mammary gland healthy epithelial and cancer cells were subjected to starvation, and differences in proliferation, migration, invasion, autophagy, and expression of autophagy-associated miRNAs were determined. Afterward, we assessed the effects of miR-218-5p modulation on the aforementioned processes. Results: Starvation-induced autophagy reduced the proliferation of all cells and increased the invasive and migratory capacity of cancer cells (p ≤ 0.05). We identified a miRNA signature related to starvation, comprising twenty-seven miRNAs. One miRNA had a significantly elevated baseline expression, while another six, including miR-218-5p, had a significantly lower basal expression in cancer cells compared to healthy cells (p ≤ 0.05). However, starvation caused significant miRNA expression changes, with miR-218-5p being upregulated specifically in cancer cells (p = 0.20–0.01). Functional studies on the role of miR-218-5p show that its inhibition decreases migration and leads to autophagosome accumulation. The study of miR-218-5p molecular targets has shown that its inhibition of sorting nexin 18 (SNX18) may act as an important regulator of the starvation-induced response in cancer cells. Conclusions: The baseline expression of miRNA related to starvation and autophagy differs between rat mammary gland cancer and healthy cells. The response to starvation also varies between cancer cells and normal cells. Starvation induces BC-specific miRNA dysregulation, affecting particularly miR-218-5p, which acts via SNX18, promoting the cancer cells’ survival. Full article

Atherosclerosis is a complex disease characterized by pathological thickening of the arterial intima. The mechanisms underlying the induction and progression of atherosclerosis are convoluted and remain under active investigation, with key components such as lipid accumulation and local inflammation being identified. Several risk factors (e.g., metabolic disorders, genetic background, diet, infections) have been shown to exacerbate disease progression, but their roles as clinically relevant markers remain to be established. Despite the growing body of evidence on the molecular pathogenesis of atherosclerosis, there is no effective preventive treatment against the development of this disease. In this review, we focus on gene targets for gene therapy as a novel potential approach to cure and prevent atherosclerosis. We critically review recent research demonstrating the therapeutic potential of viral vector-based (adeno-associated virus (AAV) and lentivirus) gene therapy for the treatment of atherosclerosis. We also summarize alternative gene targets and approaches (e.g., non-coding RNA (ncRNA), micro RNA (miRNA), small interfering RNA (siRNA), antisense oligonucleotide (ASO), CRISPR/Cas9) that aim to limit disease progression. We highlight the importance of local inflammation in the pathogenesis of atherosclerosis and propose gene targets with anti-inflammatory activity to inhibit the pathological inflammatory response. In addition, we provide perspectives on the future development of gene therapeutics and their potential applications. We anticipate that recent advances in gene therapy will help to identify new and effective targets to prevent atherosclerosis. Full article

Background: TNBC patients respond poorly to chemotherapy, leading to high mortality rates and a worsening prognosis. Here, we investigated the effect of M-I on TNBC tumor growth suppression and its potential mechanisms. Methods: Signaling pathways were analyzed to study the effect of M-I on TNBC cells (human MDA-MB-231 and mouse 4T1). We used orthotopic mouse models to examine the anti-tumor efficacy of M-I. Tumor volume and the status of tumor-associated macrophages (TAMs) were assessed by qRT-PCR or FACS analysis. Results: We found a significant dose- and time-dependent inhibition of TNBC cell proliferation following treatment with M-I. Cell cycle analysis revealed a shortened S phase in M-I-treated cells and downregulation of AURKA, PLK1, CDC25c, CDK1, and cyclinB1. Furthermore, M-I treatment reduced the expression of pSTAT3, cyclinD1, and c-Myc in TNBC cells. To evaluate the anti-tumor efficacy of M-I, we employed orthotopic TNBC mouse models and observed a significant reduction in tumor growth without measurable toxicity. Next, we analyzed RNA from control and M-I-treated tumors to further assess the status of TAMs and observed a significant decrease in M2-like macrophages in the M-I-treated group. Immortalized bone marrow-derived mouse macrophages (iMacs) exposed to conditioned media (CM) of TNBC cells with or without M-I treatment indicated that the M-I treated CM of TNBC cells significantly reduce the M2phenotype in iMacs. Mechanistically, we found that M-I specifically targets the IL-4/MAPK signaling axis to reduce immunosuppressive M2 macrophage polarization. Conclusions: Our study reveals a novel mechanism by which M-I inhibits TNBC cell proliferation by regulating intracellular signaling and altering TAMs in the tumor microenvironment and highlights its potential as a promising candidate for TNBC therapy. Full article

Ferroptosis is a type of cell death executed by phospholipid peroxidation in an iron-dependent manner. Ferroptosis plays a central role in inhibiting tumor growth, enhancing the immune response, and is now considered a strategy to combat resistance to anticancer therapies. The oncosuppressor p53 is one of the major regulators of ferroptosis and can either promote or inhibit ferroptosis, depending on the context and/or extent of the damage. p53 governs the transcription of many genes that modulate cell susceptibility to ferroptosis, using this manner of death to fulfill its role as tumor suppressor. The diverse functions of p53 are related to non-coding RNAs (ncRNAs), especially microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), since they can either regulate p53 or be regulated by p53. Therefore, an intricate metabolic network between ncRNAs and p53 ensures the correct response. In this review, we will discuss recent studies on the molecular interplay between p53-mediated ferroptosis and ncRNAs and how this contributes directly or indirectly to the outcome of ferroptosis. Full article

Glioblastoma Multiforme (GBM) is one of the most common brain tumors and is associated with aggressive tumor characteristics and extremely poor patient survival. The median survival time for GBM patients is around 12–15 months. Temozolomide (TMZ) is a key chemotherapeutic drug used in the treatment of GBM. However, at least 50% of GBM patients do not respond to TMZ, necessitating the identification of novel therapeutic strategies sensitizing patients to TMZ. In this study, we aimed to investigate the effects of two different tumor suppressor microRNAs (miR-329 and miR-449b) on cell proliferation and migration of GBM cells, and their potential for sensitizing GBM cells to TMZ. Our findings show that MiR-329/449b treatments suppressed spheroid formation and migration of GBM (LN229 and U87) cells. When miR treatments were combined with Temozolomide (TMZ), we also observed that they synergistically enhanced the suppressive effects of TMZ and inhibited the activity of clinically significant NF-KB and Src/FAK signaling pathways, making the combination therapy a viable option to treat GBM, with greater impact on patient survival. Full article

MicroRNAs belong to a class of small non-coding RNA molecules that regulate gene expression post-transcriptionally. By binding to specific mRNA sequences, microRNAs can either inhibit translation or promote transcript degradation. MicroRNA-28 (miR-28) plays a pivotal role in regulating the processes responsible for the pathogenesis of numerous diseases. Its function is contingent upon the specific type of disease and the cellular microenvironment. miR-28 can act as both an inhibitor and inducer of pathogenic processes. This article discusses the impact of miR-28 on the progression of various types of cancer, with particular emphasis on its role as a regulator of gene expression involved in cell proliferation, apoptosis, invasion, migration, and metastasis. Additionally, the article delves into the role of miR-28 in other human diseases and its influence on the processes that underlie their development. A comprehensive understanding of the precise mechanisms through which this specific microRNA exerts its regulatory functions could significantly impact the development of novel therapies. Furthermore, there is potential for miR-28 to be utilized as a diagnostic and preventative biomarker. Full article

Spinal cord injury (SCI) is a debilitating neurological condition that leads to severe disabilities, significantly reducing patients’ quality of life and imposing substantial societal and economic burdens. SCI involves a complex pathogenesis, including primary irreversible damage and secondary injury driven by neuroinflammation, apoptosis, and ischemia. Current treatments often provide limited efficacy, underscoring the urgent need for innovative therapeutic strategies. This paper aims to explore the potential use of stem cell (SC) therapy and exosome-based treatments as transformative approaches for managing SCI and mitigating associated disabilities. SCs, such as mesenchymal stem cells (MSCs), neural stem cells (NSCs), and embryonic stem cells (ESCs), demonstrate regenerative capabilities, including self-renewal, differentiation into neurons and glial cells, and modulation of the injury microenvironment. These properties enable SCs to reduce inflammation, inhibit apoptosis, and promote neuronal regeneration in preclinical models. Exosome-based therapies, derived from SCs, offer a novel alternative by addressing challenges like immune rejection and tumorigenicity. Exosomes deliver biomolecules, such as miRNAs, fostering anti-inflammatory, anti-apoptotic, and pro-regenerative effects. They have shown efficacy in improving motor function, reducing glial scarring, and enhancing axonal regrowth in SCI models. The objective of this paper is to provide a comprehensive review of SC therapy and exosome-based approaches, emphasizing their potential to revolutionize SCI management while addressing ethical concerns, immune rejection, and the need for large-scale clinical trials. These therapies hold promise for improving recovery outcomes and alleviating the profound disabilities associated with SCI. Full article

GBM is the most common and aggressive primary brain tumor in adults, characterized by low survival rates, high recurrence, and resistance to conventional therapies. Traditional diagnostic and therapeutic methods remain limited due to the difficulty in permeating the blood–brain barrier (BBB), diffuse tumor cell infiltration, and tumor heterogeneity. In recent years, nano-based technologies have emerged as innovative approaches for the detection and treatment of GBM. A wide variety of nanocarriers, including dendrimers, liposomes, metallic nanoparticles, carbon nanotubes, carbon dots, extracellular vesicles, and many more demonstrate the ability to cross the BBB, precisely deliver therapeutic agents, and enhance the effects of radiotherapy and immunotherapy. Surface functionalization, peptide modification, and cell membrane coating improve the targeting capabilities of nanostructures toward GBM cells and enable the exploitation of their photothermal, magnetic, and optical properties. Furthermore, the development of miRNA nanosponge systems offers the simultaneous inhibition of multiple tumor growth mechanisms and the modulation of the immunosuppressive tumor microenvironment. This article presents current advancements in nanotechnology for GBM, with a particular focus on the characteristics and advantages of specific groups of nanoparticles, including their role in radiosensitization. Full article

E3 ubiquitin ligases and deubiquitinating enzymes (DUBs) are pivotal regulators of bone homeostasis, orchestrating osteoblast differentiation, proliferation, and osteoclast activity by controlling protein degradation and stability. This review delineates the roles of key E3 ligases (e.g., Smurf1, Smurf2, TRIM family) and DUBs (e.g., USP family) in bone formation and resorption. E3 ligases such as Smurf1/2 inhibit osteogenesis by degrading BMP/Smad signaling components, while TRIM proteins and HERC ligases promote osteoblast differentiation. Conversely, DUBs like USP2 and USP34 stabilize β-catenin and Smad1/RUNX2, enhancing osteogenic pathways, whereas USP10 and USP12 suppress differentiation. Dysregulation of these enzymes contributes to osteoporosis, fracture non-union, and other bone disorders. The interplay between ubiquitination and deubiquitination, alongside the regulatory role of miRNA and environmental factors, underscores their therapeutic potential. Future research should focus on developing therapies targeting E3 ubiquitin ligases, deubiquitinases, miRNA regulators, and small-molecule inhibitors to restore bone homeostasis in osteoporosis and fracture healing disorders. Full article

Adipocyte differentiation is a complex process in which pluripotent mesenchymal stem cells (MSCs) differentiate and develop into mature fat cells, also known as adipocytes. This process is controlled by various transcription factors, hormones, and signaling molecules that regulate the development of these cells. Recently, an increasing number of non-coding RNAs (ncRNAs), especially microRNAs (miRNAs), have been established to be involved in the regulation of many biological processes, including adipocyte differentiation, development, metabolism, and energy homeostasis of white and brown adipose tissue. Several in vitro and in vivo studies reported the significant role of ncRNAs in either promoting or inhibiting adipocyte differentiation into white or brown fat cells by targeting specific transcription factors and regulating the expression of key adipogenic genes. Identifying the function of ncRNAs and their subsequent targets contributes to our understanding of how these molecules can be used as potential biomarkers and tools for therapies against obesity, diabetes, and other diseases related to obesity. This could also contribute to advancements in tissue-engineering based treatments. In this review, we intended to present an up-to-date comprehensive literature overview of the role of ncRNAs, including miRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), focusing particularly on miRNAs, in regulating the differentiation and development of cells into white and brown adipose tissue. In addition, we further discuss the potential use of these molecules as biomarkers for the development of novel therapeutic strategies for future personalized treatment options for patients. Full article

Papillary thyroid carcinoma (PTC) is the most common subtype of thyroid malignancy, and its progression is closely associated with patient outcomes. This study investigated the role of the long non-coding RNA LINC02560 in the pathogenesis and aggressiveness of PTC through cell culture, transfection, RT-qPCR, Western blot analysis, and various functional assays, such as MTT, EdU, colony formation, wound healing, and Transwell migration assays. Our results revealed a significant upregulation of LINC02560 in PTC tissues, correlating with poor prognosis in affected patients. Functional analyses demonstrated that silencing of LINC02560 markedly inhibited the proliferation, migration, and invasion of the PTC cell lines, KTC-1, and BCPAP, whereas overexpression promoted these aggressive traits. Mechanistically, LINC02560 acted as a competitive endogenous RNA, sponging miR-505-5p and alleviating its suppression on PDE4C degradation, thereby activating the P-AKT and epithelial–mesenchymal transition (EMT) signaling pathways. Additionally, HNF4α was identified as a transcription factor capable of enhancing the expression of LINC02560. In conclusion, our findings elucidate the critical HNF4α/LINC02560/miR-505-5p/PDE4C axis in PTC pathology, presenting this regulatory network as a promising biomarker combination and potential therapeutic target to improve patient outcomes and survival rates, warranting further clinical investigation to validate these insights and support the development of targeted therapies in PTC management. Full article

Renal cell carcinoma (RCC) is the most lethal malignancy of the urinary system, with limited treatment options due to drug resistance and the adverse effects associated with current therapies. This review aims to systematically examine the therapeutic potential of flavonoids, which are natural polyphenolic compounds possessing anti-inflammatory, antioxidant, and anticancer properties, in the context of RCC treatment. We summarize the anticancer activities of 26 natural flavonoids, classified into six subclasses, and explore their mechanisms of action, including the inhibition of tumor cell proliferation, migration, and invasion, as well as the induction of apoptosis, autophagy, and ferroptosis. Particular attention is paid to their modulation of key signaling pathways such as the JAK/STAT3, PI3K/Akt/mTOR, and miRNA-related axes, including miR-21/YAP1 and miR-324-3p/GPX4, providing a molecular basis for their anti-RCC activity. We also address several pharmacological challenges that limit the clinical application of flavonoids, including poor bioavailability, metabolic instability, and potential toxicity. Emerging solutions such as novel flavonoid derivatives, advanced drug delivery systems, and rational combination therapy strategies are also discussed. Current clinical evidence, including a phase II trial of flavopiridol in advanced RCC, highlights the potential but also the need for further validation. In conclusion, flavonoids offer a promising approach to improving RCC treatment. Future research should focus on optimizing their therapeutic efficacy and ensuring their safe clinical translation, with the goal of achieving personalized and minimally invasive cancer therapies. Full article

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motor neurons, which causes muscle atrophy. Genetic forms of ALS are recorded only in 10% of cases. However, over the past decade, studies in genetics have substantially contributed to our understanding of the molecular mechanisms underlying ALS. The identification of key mutations such as SOD1, C9orf72, FUS, and TARDBP has led to the development of targeted therapy that is gradually being introduced into clinical trials, opening up a broad range of opportunities for correcting these mutations. In this review, we aimed to present an extensive overview of the currently known mechanisms of motor neuron degeneration associated with mutations in these genes and also the gene therapy methods for inhibiting the expression of their mutant proteins. Among these, antisense oligonucleotides, RNA interference (siRNA and miRNA), and gene-editing (CRISPR/Cas9) methods are of particular interest. Each has shown its efficacy in animal models when targeting mutant genes, whereas some of them have proven to be efficient in human clinical trials. Full article

The therapeutic potential of presumed cardiac progenitor cells (CPCs) in heart regeneration has garnered significant interest, yet clinical trials have revealed limited efficacy due to challenges in cell survival, retention, and expansion. Priming CPCs to survive the hostile hypoxic environment may be key to enhancing their regenerative capacity. We demonstrate that microRNA-210 (miR-210), known for its role in hypoxic adaptation, significantly improves CPC survival by inhibiting apoptosis through the downregulation of Casp8ap2, a ~40% reduction in caspase activity, and a ~90% decrease in DNA fragmentation. Contrary to the expected induction of Bnip3-dependent mitophagy by hypoxia, miR-210 did not upregulate Bnip3, indicating a distinct anti-apoptotic mechanism. Instead, miR-210 reduced markers of mitophagy and increased mitochondrial biogenesis and oxidative metabolism, suggesting a role in metabolic reprogramming. Furthermore, miR-210 enhanced the secretion of paracrine growth factors from CPCs, with a ~1.6-fold increase in the release of stem cell factor and of insulin growth factor 1, which promoted in vitro endothelial cell proliferation and cardiomyocyte survival. These findings elucidate the multifaceted role of miR-210 in CPC biology and its potential to enhance cell-based therapies for myocardial repair by promoting cell survival, metabolic adaptation, and paracrine signalling. Full article

Background: Adoptive cell therapy (ACT), including CAR-T and TCR-T therapies, shows promise for cancer treatment, depending on infused T cell expansion, persistence and activity. We previously characterized four T-cell subsets (T_N, T_SCM, T_CM and T_EM) and their miRNA profiles. Objectives: This study investigates miR-143-3p’s role in T cell differentiation. Methods: Using qPCR, we analyzed miR-143-3p expression. Target genes were validated by dual-luciferase assays. Functional assays assessed differentiation markers, proliferation, apoptosis and cytokine secretion. Results: miR-143-3p was upregulated in early-differentiated T_SCM but downregulated during progression. We confirmed ABL2 and PAG1 as direct targets suppressed by miR-143-3p. Overexpression increased early markers (LEF1, CCR7 and CD62L) while decreasing late markers (EOMES, KLRG1 and CD45RO). It also enhanced proliferation, reduced apoptosis and suppressed cytokine secretion. Conclusions: miR-143-3p promotes T_SCM differentiation and inhibits progressive differentiation by targeting ABL2/PAG1, suggesting new ACT optimization strategies. Full article