Search Results (541)

Fungi, from saprophytes to pathogens, face predictable daily fluctuations in light, temperature, humidity, and nutrient availability. To cope, they have evolved an internal circadian clock that confers a major adaptive advantage. This review critically synthesizes current knowledge on the molecular architecture and physiological relevance of fungal circadian systems, moving beyond the canonical Neurospora crassa model to explore the broader phylogenetic diversity of timekeeping mechanisms. We examine the core transcription-translation feedback loop (TTFL) centered on the FREQUENCY/WHITE COLLAR (FRQ/WCC) system and contrast it with divergent and non-canonical oscillators, including the metabolic rhythms of yeasts and the universally conserved peroxiredoxin (PRX) oxidation cycles. A central theme is the clock’s role in gating cellular defenses against oxidative, osmotic, and nutritional stress, enabling fungi to anticipate and withstand environmental insults through proactive regulation. We provide a detailed analysis of chrono-pathogenesis, where the circadian control of virulence factors aligns fungal attacks with windows of host vulnerability, with a focus on experimental evidence from pathogens like Botrytis cinerea, Fusarium oxysporum, and Magnaporthe oryzae. The review explores the downstream pathways—including transcriptional cascades, post-translational modifications, and epigenetic regulation—that translate temporal signals into physiological outputs such as developmental rhythms in conidiation and hyphal branching. Finally, we highlight critical knowledge gaps, particularly in understudied phyla like Basidiomycota, and discuss future research directions. This includes the exploration of novel clock architectures and the emerging, though speculative, hypothesis of “chrono-therapeutics”—interventions designed to disrupt fungal clocks—as a forward-looking concept for managing fungal infections. Full article

Oligodendrocyte precursor cells (OPCs) are a distinct and dynamic glial population that retain proliferative and migratory capacities throughout life. While traditionally recognized for differentiating into oligodendrocytes (OLs) and generating myelin to support rapid nerve conduction, OPCs are now increasingly appreciated for their diverse and non-canonical roles in the central nervous system (CNS), including direct interactions with neurons. A notable feature of OPCs is their expression of diverse ion channels that orchestrate essential cellular functions, including proliferation, migration, and differentiation. Given their widespread distribution across the CNS, OPCs are increasingly recognized as active contributors to the development and progression of various neurological disorders. This review aims to present a detailed summary of the physiological and pathological functions of ion channels in OPCs, emphasizing their contribution to CNS dysfunction. We further highlight recent advances suggesting that ion channels in OPCs may serve as promising therapeutic targets across a broad range of disorders, including, but not limited to, multiple sclerosis (MS), spinal cord injury, amyotrophic lateral sclerosis (ALS), psychiatric disorders, Alzheimer’s disease (AD), and neuropathic pain (NP). Finally, we discuss emerging therapeutic strategies targeting OPC ion channel function, offering insights into potential future directions in the treatment of CNS diseases. Full article

Transforming growth factor-β (TGF-β) is a key protein family member that includes activins, inhibins, and bone morphogenetic proteins (BMPs). It is essential in numerous biological processes, such as chemotaxis, apoptosis, differentiation, growth, and cell migration. TGF-β receptors initiate signaling through two primary pathways: the canonical pathway involving Smad proteins and non-canonical pathways that utilize alternative signaling mechanisms. When TGF-β signaling is disrupted, it has been shown to contribute to the development of various diseases, including cancer. Initially, TGF-β effectively inhibits the cell cycle and promotes apoptosis. However, its role can transition to facilitating tumor growth and metastasis as the disease progresses. Moreover, TGF-β drives cancer progression through epithelial–mesenchymal transition (EMT), modulation of factor expression, and evasion of immune responses. This complexity establishes the need for further research, particularly into pharmacological agents targeting TGF-β, which are emerging as promising therapeutic options. Current clinical and preclinical studies are making significant strides toward mitigating the adverse effects of TGF-β. This underscores the critical importance of understanding its underlying mechanisms to enhance treatment effectiveness and improve survival rates for cancer patients. Full article

The protein p53, often referred to as the “guardian of the genome,” is essential for preserving cellular balance and preventing cancerous transformations. As one of the most commonly altered genes in human cancers, its impaired function is associated with tumor initiation, development, and resistance to treatment. Exploring the diverse roles of p53, which include regulating the cell cycle, repairing DNA, inducing apoptosis, reprogramming metabolism, and modulating immunity, provides valuable insights into cancer mechanisms and potential treatments. This review integrates recent findings on p53′s dual nature, functioning as both a tumor suppressor and an oncogenic promoter, depending on the context. Wild-type p53 suppresses tumors by inducing cell cycle arrest or apoptosis in response to genotoxic stress, while mutated variants often lose these functions or gain novel pro-oncogenic activities. Emerging evidence highlights p53′s involvement in non-canonical pathways, such as regulating tumor microenvironment interactions, metabolic flexibility, and immune evasion mechanisms. For instance, p53 modulates immune checkpoint expression and influences the efficacy of immunotherapies, including PD-1/PD-L1 blockade. Furthermore, advancements in precision diagnostics, such as liquid biopsy-based detection of p53 mutations and AI-driven bioinformatics tools, enable early cancer identification and stratification of patients likely to benefit from targeted therapies. Therapeutic strategies targeting p53 pathways are rapidly evolving. Small molecules restoring wild-type p53 activity or disrupting mutant p53 interactions, such as APR-246 and MDM2 inhibitors, show promise in clinical trials. Combination approaches integrating gene editing with synthetic lethal strategies aim to exploit p53-dependent vulnerabilities. Additionally, leveraging p53′s immunomodulatory effects through vaccine development or adjuvants may enhance immunotherapy responses. In conclusion, deciphering p53′s complex biology underscores its unparalleled potential as a biomarker and therapeutic target. Integrating multi-omics analyses, functional genomic screens, and real-world clinical data will accelerate the translation of p53-focused research into precision oncology breakthroughs, ultimately improving patient outcomes. Full article

Adenosine receptors (ARs) are G protein-coupled receptors that are widely expressed across tissues, traditionally associated with cardiovascular, neurological, and immune regulation. Recent studies, however, have highlighted their non-canonical functions, revealing critical roles in metabolism, immunometabolism, and epigenetic regulation. AR subtypes, particularly A2A and A2B, modulate glucose and lipid metabolism, mitochondrial activity, and energy homeostasis. In immune cells, AR signaling influences metabolic reprogramming and polarization through key regulators such as mTOR, AMPK, and HIF-1α, contributing to immune tolerance or activation depending on the context. Additionally, ARs have been implicated in epigenetic modulation, affecting DNA methylation, histone acetylation, and non-coding RNA expression via metabolite-sensitive mechanisms. Therapeutically, AR-targeting agents are being explored for cancer and chronic inflammatory diseases. While clinical trials with A2A antagonists in oncology show encouraging results, challenges remain due to receptor redundancy, systemic effects, and the need for tissue-specific selectivity. Future strategies involve biased agonism, allosteric modulators, and combination therapies guided by biomarker-based patient stratification. Overall, ARs are emerging as integrative hubs connecting extracellular signals with cellular metabolic and epigenetic machinery. Understanding these non-canonical roles may unlock novel therapeutic opportunities across diverse disease landscapes. Full article

The Wnt signaling pathway plays a critical role in regulating normal hematopoiesis and immune cell development. However, its dysregulation has emerged as a key driver of leukemogenesis. Leukemic stem cells exploit aberrant Wnt signaling to sustain self-renewal, evade apoptosis, and promote unchecked proliferation. In this review, we highlight the dual roles of canonical and non-canonical Wnt pathways in acute leukemia, emphasizing their distinct and overlapping contributions to disease progression. We also evaluate current preclinical and clinical strategies targeting Wnt signaling, identifying both promising advances and persistent obstacles to therapeutic translation. By elucidating the molecular mechanisms underlying Wnt pathway dysregulation in leukemic cells, this review underscores the potential of Wnt-directed therapies as a novel class of interventions to improve outcomes for patients with acute leukemia. Full article

Recent insights into the p53-MDM2 nexus have advanced deeper understanding of their regulation and potent impact on cancer heterogeneity. The roles of nuclear phosphoinositide (PIP_ns) in modulating this pathway are emerging as a key mechanism. Here, we dissect the molecular mechanisms by which nuclear PIP_ns stabilize p53 through the recruitment of small heat shock proteins (sHSPs), activate the nuclear phosphatidylinositol 3-kinase (PI3K)-AKT signaling cascade, and modulate MDM2 function to regulate the p53-MDM2 interaction. We propose potential mechanisms by which nuclear PIP_ns coordinate signaling with nuclear p53, AKT, and MDM2. Ultimately, we highlight that nuclear PIP_ns serve as a ‘third messenger’ within the p53-MDM2 axis, expanding the current framework of non-canonical nuclear signaling in cancer biology. Full article

Testicular germ cell tumors (TGCTs) are the most common malignancies affecting young men between the ages of 14 and 44, accounting for about 95% of all testicular cancers. Despite being relatively rare compared to other cancers (~3.0 cases per 100,000 population, with high worldwide variability), TGCTs’ incidence is increasing, particularly in industrialized countries. The initial phase of TGCT diagnosis is performed by detecting in the blood the presence of three proteins, i.e., alpha-fetoprotein (AFP), lactate dehydrogenase (LDH), and human chorionic gonadotropin (hCG). Despite these proteins being defined as markers of TGCTs, they present limitations in specificity. Indeed, AFP is not elevated in pure seminomas; LDH serum levels can be elevated in other conditions, such as liver disease or tissue damage, and hCG can be elevated in both seminomas and non-seminomas, reducing its ability to differentiate between tumor types. However, the existence of hCG variants, characterized by distinct glycosylation profiles that are differentially expressed in TGCT types and subtypes, may increase the diagnostic and prognostic potential of this hormone. Furthermore, emerging molecular biomarkers, including miRNAs and tumor cells-related epigenetic status, may offer new promising alternatives to improve diagnostic accuracy. Nonetheless, standardized diagnostic protocols still need to be implemented. Finally, understanding the biological roles of hCG isoforms and their “canonical” (e.g., LHCGR) and “non-canonical” (e.g., TGF-βR) receptor interactions may help in understanding tumor biology and therapeutic targeting. Full article

A sudden increase in ambient oxygen concentration after birth forces the metabolic switch from anaerobic glycolysis to oxidative phosphorylation, which contributes to the rapid decline of cardiomyocyte proliferation. Lactate dehydrogenase A (LDHA), a metabolic enzyme normally localized in the cytoplasm, has been reported to regulate cardiomyocyte proliferation via inducing metabolic reprogramming. Nuclear LDHA has been observed in multiple proliferative cells, whereas the role of LDHA nuclear translocation in cardiomyocyte proliferation remains unresolved. Here we found that the expression of nuclear LDHA was induced both in the infarct area of myocardial infarction (MI) in mice and hypoxic cardiomyocytes in vitro. Mechanically, mild hypoxia prompted metabolic reprogramming which motivated cardiomyocyte proliferation by alleviating reactive oxygen species (ROS), while severe hypoxia coincided with oxidative stress that induced cardiomyocyte cell cycle arrest. Interestingly, LDHA nuclear translocation in cardiomyocytes occurred in response to oxidative stress, and blocking of nuclear LDHA resulted in elevated ROS generation. Collectively, our findings uncover a non-canonical role of nuclear LDHA in maintaining redox balance and resisting cardiomyocyte cell cycle arrest. Full article

The DNA of all living organisms is a common matrix for both replication and transcription processes. This sometimes leads to inevitable collisions between DNA replication and transcription machinery. There is plethora of evidence demonstrating that such collisions (or TRCs) are one of the most common and significant reasons for genomic instability. One of the key outcomes of TRCs is the accumulation of non-canonical DNA secondary structures, including R-loops. R-loops are three-stranded DNA–RNA hybrids with a displaced third single-stranded DNA fragment. Although R-loops are thought to play several functional roles in biological processes, an imbalance in their metabolism has been proven to have severe consequences. In this review, we attempt to summarize the current knowledge of the participants in the process of R-loop regulation in cells, with an emphasis on eukaryotic systems. We also touch upon the conditions favoring TRCs and the possible ways of dealing with these conflicts. Full article

Circular RNAs (circRNAs) are covalently closed RNA molecules generated through a non-canonical splicing event known as back-splicing. This particular class of non-coding RNAs has attracted growing interest due to its evolutionary conservation across eukaryotes, high expression in the central nervous system, and frequent dysregulation in various pathological conditions, including cancer. Traditionally, circRNAs have been characterised by their ability to function as microRNA (miRNA) and protein sponges. However, recent discoveries from multiple research groups have uncovered a novel and potentially transformative mechanism of action: the direct interaction of circRNAs with messenger RNAs (mRNAs) to regulate their fate. These interactions can influence mRNA stability and translation, revealing a new layer of post-transcriptional gene regulation. In this review, we present and analyse the latest evidence supporting the emerging role of circRNAs in diverse biological contexts. We highlight the growing body of research demonstrating circRNA-mRNA interactions as a functional regulatory mechanism and explore their involvement in key physiological and pathophysiological processes. Understanding this novel mechanism expands our knowledge of RNA-based regulation and opens new opportunities for therapeutic strategies targeting circRNA-mRNA networks in human disease. Full article

Autophagy is an essential eukaryotic catabolic process through which damaged or superfluous cellular components are degraded and recycled via the formation of double-membrane autophagosomes. In plants, autophagy-related genes (ATGs) are primarily expressed in the cytoplasm and are responsible for orchestrating distinct stages of autophagosome biogenesis. Among these, ATG8 proteins, orthologous to the mammalian LC3 family, are conserved ubiquitin-like modifiers that serve as central hubs in selective autophagy regulation. Although ATG8 proteins are localized in both the cytoplasm and nucleus, their functions within the nucleus remain largely undefined. In the present study, the ATG8-interacting motif (AIM) was identified and functionally characterized in the potato ATG8 homolog (StATG8), demonstrating its capacity for selective target recognition. StATG8 was shown to form both homodimeric and heterodimeric complexes with other ATG8 isoforms, implying a broader regulatory potential within the ATG8 family. Notably, StATG8 was found to interact with the Ralstonia solanacearum type III effector PopP2, a nuclear-localized acetyltransferase, suggesting a possible role in effector recognition within the nucleus. In addition, interactions between StATG8 and transcription factors AtWRKY40 and AtWRKY60 were detected in both cytoplasmic autophagosomes and the nuclear compartment. These observations provide novel insights into the noncanonical, nucleus-associated roles of plant ATG8 proteins. The nuclear interactions with pathogen effectors and transcriptional regulators suggest that ATG8 may function beyond autophagic degradation, contributing to the regulation of nuclear signaling and plant immunity. These findings offer a foundational basis for further investigation into the functional diversification of ATG8 in plant cellular compartments. Full article

The envelope stress response in Escherichia coli is primarily governed by the sigma factor RpoE (σ^E), which activates protective genes upon membrane perturbation. Under non-stress conditions, σ^E is sequestered by its anti-sigma factor RseA. In this study, we identify an unexpected role for the nitric-oxide-sensing repressor NsrR in dampening σ^E activity and repressing σ^E-dependent small RNAs, including rybB, micA, and micL. Overexpression of nsrR represses transcription from σ^E-dependent promoters and phenocopies σ^E inactivation, resulting in filamentous morphology and growth defects. Conversely, ΔnsrR de-represses σ^E targets, with additive effects in rseA mutants—supporting an RseA-independent regulatory role. Time-course analysis shows NsrR represses σ^E activity, with kinetics comparable to those of RseA. While in vitro assays failed to detect robust NsrR binding to σ^E target promoters, NsrR directly interacts with σ^E in bacterial two-hybrid assays. Structural modeling using AlphaFold3 supports a plausible NsrR–RpoE interaction interface. These findings suggest that NsrR functions as a noncanonical anti-sigma-like modulator of σ^E, integrating redox and envelope stress signals to maintain membrane homeostasis. Full article

Thymic epithelial tumors (TETs) display heterogeneous histology and often unpredictable clinical behavior. The Hippo signaling pathway has been implicated in tumorigenesis, but its role in TETs remains poorly characterized. We performed the first comprehensive immunohistochemical analysis of core and upstream Hippo pathway components—YAP1, active YAP (AYAP), TAZ, LATS1, MOB1A, MST1, SAV1, and TEAD4—in 77 TETs. Associations with clinicopathological parameters and survival were explored. We observed widespread expression of Hippo components in TETs with significant associations among molecules and differences in subcellular localization and expression in normal tissue. Early stage TETs showed higher nuclear YAP1 (p = 0.032) and AYAP (p = 0.007), while cytoplasmic MST1 (p = 0.002), LATS1 (p = 0.007), MOB1A (p = 0.033) and TEAD4 (p < 0.001) correlated with advanced stage. Cytoplasmic MST1 (p = 0.014), LATS1 (p < 0.001) and TEAD4 (p = 0.005) were associated with histological aggressiveness. Cytoplasmic TEAD4 overexpression was associated with poorer overall survival (log-rank, <70% versus ≥70%, p = 0.003). Our findings provide novel insights into the differential regulation and compartmentalization of Hippo components in TETs. While indolent tumors show features that are consistent with partial Hippo inactivation, more aggressive phenotypes exhibit reduced nuclear YAP/TAZ and altered TEAD4 compartmentalization, suggesting a context-dependent Hippo signaling state. Cytoplasmic TEAD4 emerges as a potential adverse prognosticator, indicating involvement in non-canonical or Hippo-independent mechanisms. Full article

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with a poor prognosis. Activating mutations in the FLT3 gene occur in approximately 30% of AML cases, with internal tandem duplications in the juxtamembrane domain (FLT3-ITD; 75%) and mutations in the tyrosine kinase domain (FLT3-TKD; 25%). FLT3-ITD mutations are linked to poor prognosis and offer significant clinical predictive value, whereas the implications of FLT3-TKD mutations are less understood. The Hedgehog–Gli pathway is an established therapeutic target in AML, and emerging evidence suggests crosstalk between FLT3-ITD signaling and Gli expression regulation via non-canonical mechanisms. Post-translational modifications involving myristic and palmitic acids regulate various cellular processes, but their role in AML remains poorly defined. In this study, we investigated the role of fatty acid synthase (FASN), which synthesizes myristic and palmitic acids and catalyzes palmitoyl-acyltransferation, in regulating FLT3-ITD-Gli signaling. FASN knockdown using shRNA and the FASN inhibitor TVB-3166 was performed in FLT3-ITD-mutated AML cell lines (MOLM13, MV411) and Baf3-FLT3-ITD cells. The impact of FASN inhibition was assessed through Western blot and kinome profiling, while biological implications were evaluated by measuring cell viability and proliferation. FASN inhibition resulted in reduced levels of phospho-Akt (pAkt) and phospho-S6 kinase (pS6) and decreased expression of Hedgehog–Gli1, confirming non-canonical regulation of Gli by FLT3-ITD signaling. Combining TVB-3166 with the Gli inhibitor GANT61 significantly reduced the survival of MOLM13 and MV411 cells. Full article