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Liquid-liquid phase separation (LLPS) is a fundamental biophysical process driving the formation of dynamic biomolecular condensates, which spatially organize cellular biochemistry without membrane delimitation. These condensates arise from multivalent, weak interactions among intrinsically disordered proteins, modular interaction motifs, and RNA scaffolds, enabling highly tunable and reversible compartmentalization of biomolecules. This phase behavior regulates critical cellular functions such as gene expression, signal transduction, and stress response, while its dysregulation contributes to pathological aggregation and disease. Recent advances leverage LLPS principles to design synthetic condensates with controllable composition, properties, and activities. Combining structural insights, quantitative phase behavior, and synthetic biology tools, engineered condensates have been developed for enhanced catalysis, metabolic control, targeted drug delivery, and biosensing. This review summarizes the molecular mechanisms, design strategies, and translational prospects of LLPS-mediated condensates, thereby paving the way for future exploration at the interface of cellular biophysics and bioengineering. Show less

N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic mRNA and has emerged as a pivotal regulator of gene expression at the post-transcriptional level. In the tumor immune microenvironment, tumor-associated macrophages (TAMs) represent a highly plastic and heterogeneous population that profoundly influences cancer progression, immune evasion, and therapeutic response. Recent studies have uncovered that m6A modification, mediated by dynamic “writers,” “erasers,” and “readers,” exerts critical regulatory effects on TAM differentiation, polarization, and functional reprogramming. By modulating the stability, translation, and decay of transcripts involved in inflammatory signaling, metabolic adaptation, and immune checkpoints, m6A shapes the balance between tumor-promoting (M2-like) and tumor-suppressive (M1-like) macrophage phenotypes. Moreover, dysregulation of m6A machinery in TAMs has been linked to the suppression of anti-tumor immunity and resistance to immunotherapy, highlighting its translational potential as a therapeutic target. This review summarizes current advances in understanding the roles and mechanisms of m6A modification in TAM biology, discusses its implications in tumor immunity, and outlines the challenges and opportunities of targeting the m6A–TAM axis for cancer treatment. Show less

N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic mRNA and has emerged as a pivotal regulator of gene expression at the post-transcriptional level. In the tumor immune microenvironment, tumor-associated macrophages (TAMs) represent a highly plastic and heterogeneous population that profoundly influences cancer progression, immune evasion, and therapeutic response. Recent studies have uncovered that m6A modification, mediated by dynamic “writers,” “erasers,” and “readers,” exerts critical regulatory effects on TAM differentiation, polarization, and functional reprogramming. By modulating the stability, translation, and decay of transcripts involved in inflammatory signaling, metabolic adaptation, and immune checkpoints, m6A shapes the balance between tumor-promoting (M2-like) and tumor-suppressive (M1-like) macrophage phenotypes. Moreover, dysregulation of m6A machinery in TAMs has been linked to the suppression of anti-tumor immunity and resistance to immunotherapy, highlighting its translational potential as a therapeutic target. This review summarizes current advances in understanding the roles and mechanisms of m6A modification in TAM biology, discusses its implications in tumor immunity, and outlines the challenges and opportunities of targeting the m6A–TAM axis for cancer treatment. Show less

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Institutes of Health (NIH) Introduction The prevalence of obesity continues to rise to unprecedented levels, and with it, a corresponding increase in the incidence of cardiovascular disease (CVD). While obesity is indeed accepted as one of the most prominent risk factors for CVD, the precise molecular mechanisms by which aberrant metabolism is linked to cardiovascular function remain incompletely understood. One prevailing hypothesis is that overproduction of reactive oxygen species (ROS) from increased metabolism significantly contributes to endothelial dysfunction, which precedes many cardiovascular events such as atherosclerosis and stroke. Purpose In this study, we hypothesized that a receptor for advanced glycation end products, Galectin-3 (GAL3), acts as a metabolic sensor and regulates endothelial ROS production in obesity. Methods Obese db/db mice were crossed with mice lacking GAL3, and endothelial gene expression, microvascular reactivity, and ROS production were assessed. Results We demonstrate that NADPH Oxidase I (NOX1), the predominant source of endothelial superoxide production, is down-regulated by GAL3 deletion, thereby rescuing endothelial function and ameliorating endothelial ROS production in obesity. Furthermore, we demonstrate that GAL3-mediated NOX1 over-expression is amenable to improvements in metabolic status, such as lowering blood glucose with metformin, improving glucose handling by augmenting muscle mass, or improving insulin signaling through deletion of Protein Tyrosine Phosphatase 1B (PTP1B). Conclusion Taken together, these data demonstrate that the overproduction of superoxide by endothelial NOX1 is regulated by the metabolic sensor GAL3 in obesity, leading to endothelial dysfunction and CVD. This pathway presents an attractive target for therapeutic intervention to break the link between aberrant metabolism in obesity and its corresponding vascular pathologies. Show less

Hydrogen peroxide (H2 O2 ) is an important reactive oxygen species that plays a major role in redox signaling. Although H2 O2 is known to regulate gene expression and affect multiple cellular processes, the characteristics and mechanisms of such transcriptional regulation remain to be defined. In this study, we utilized transcriptome sequencing to determine the global changes of mRNA and lncRNA transcripts induced by H2 O2 in human pancreatic normal epithelial (HPNE) and pancreatic cancer (PANC-1) cells. Promoter analysis using PROMO and TRRUST revealed that mRNAs and lncRNAs largely shared the same sets of transcription factors in response to ROS stress. Interestingly, promoters of the upregulated genes were similar to those of the downregulated transcripts, suggesting that the H2 O2 -responding promoters are conserved but they alone do not determine the levels of transcriptional outputs. We also found that H2 O2 induced significant changes in molecules involved in the pathways of RNA metabolism, processing, and transport. Detailed analyses further revealed a significant difference between pancreatic cancer and noncancer cells in their response to H2 O2 stress, especially in the transcription of genes involved in cell-cycle regulation and DNA repair. Our study provides new insights into RNA transcriptional regulation upon ROS stress in cancer and normal cells. Transcription of mRNA and lncRNA. Antioxidants 2022, 11, 495. https:// Show less

In the most recent decades, oxaliplatin has been used as a chemotherapeutic agent for colorectal cancer and other malignancies as well. Oxaliplatin interferes with tumor growth predominantly exerting its action in DNA synthesis inhibition by the formation of DNA-platinum adducts that, in turn, leads to cancer cell death. On the other hand, unfortunately, this interaction leads to a plethora of systemic side effects, including those affecting the peripheral and central nervous system. Oxaliplatin therapy has been associated with acute and chronic neuropathic pain that induces physicians to reduce the dose of medication or discontinue treatment. Recently, the capability of oxaliplatin to alter the genetic and epigenetic profiles of the nervous cells has been documented, and the understanding of gene expression and transcriptional changes may help to find new putative treatments for neuropathy. The present article is aimed to review the effects of oxaliplatin on genetic and epigenetic mechanisms to better understand how to ameliorate neuropathic pain in order to enhance the anti-cancer potential and improve patients' quality of life. Show less

Nucleophosmin (NPM1) is a ubiquitously expressed nucleolar protein involved in ribosome biogenesis, the maintenance of genomic integrity and the regulation of the ARF-p53 tumor-suppressor pathway among multiple other functions. Mutations in the corresponding gene cause a cytoplasmic dislocation of the NPM1 protein. These mutations are unique to acute myeloid leukemia (AML), a disease characterized by clonal expansion, impaired differentiation and the proliferation of myeloid cells in the bone marrow. Despite our improved understanding of NPM1 mutations and their consequences, the underlying leukemia pathogenesis is still unclear. Recent studies that focused on dysregulated gene expression in AML with mutated NPM1 have shed more light into these mechanisms. In this article, we review the current evidence on normal functions of NPM1 and aberrant functioning in AML, and highlight investigational strategies targeting these mutations. Show less

The methylation of arginine residues regulates gene expression, DNA repair, growth factor signalling and liquid–liquid phase separation. Targeting this modification can thus be therapeutically relevant and inhibitors of arginine methylation are being tested in clinical trials, especially for neurodegenerative diseases and cancer. Show less

The deregulation of gene expression is a characteristic of cancer cells, and malignant cells require very high levels of transcription to maintain their cancerous phenotype and survive. Therefore, components of the basal transcription machinery may be considered as targets to preferentially kill cancerous cells. TFIIH is a multisubunit basal transcription factor that also functions in nucleotide excision repair. The recent discoveries of some small molecules that interfere with TFIIH and that preferentially kill cancer cells have increased researchers' interest to elucidate the complex mechanisms by which TFIIH operates. In this review, we summarize the knowledge generated during the 25 years of TFIIH research, highlighting the recent advances in TFIIH structural and mechanistic analyses that suggest the potential of TFIIH as a target for cancer treatment. Show less