Search Results (554)

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

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

Background/Objectives: The RTK-RAS signaling cascade is a central axis in colorectal cancer (CRC) pathogenesis, governing cellular proliferation, survival, and therapeutic resistance. Somatic alterations in key pathway genes—including KRAS, NRAS, BRAF, and EGFR—are pivotal to clinical decision-making in precision oncology. However, the integration of these genomic events with clinical and demographic data remains hindered by fragmented resources and a lack of accessible analytical frameworks. To address this challenge, we developed AI-HOPE-RTK-RAS, a domain-specialized conversational artificial intelligence (AI) system designed to enable natural language-based, integrative analysis of RTK-RAS pathway alterations in CRC. Methods: AI-HOPE-RTK-RAS employs a modular architecture combining large language models (LLMs), a natural language-to-code translation engine, and a backend analytics pipeline operating on harmonized multi-dimensional datasets from cBioPortal. Unlike general-purpose AI platforms, this system is purpose-built for real-time exploration of RTK-RAS biology within CRC cohorts. The platform supports mutation frequency profiling, odds ratio testing, survival modeling, and stratified analyses across clinical, genomic, and demographic parameters. Validation included reproduction of known mutation trends and exploratory evaluation of co-alterations, therapy response, and ancestry-specific mutation patterns. Results: AI-HOPE-RTK-RAS enabled rapid, dialogue-driven interrogation of CRC datasets, confirming established patterns and revealing novel associations with translational relevance. Among early-onset CRC (EOCRC) patients, the prevalence of RTK-RAS alterations was significantly lower compared to late-onset disease (67.97% vs. 79.9%; OR = 0.534, p = 0.014), suggesting the involvement of alternative oncogenic drivers. In KRAS-mutant patients receiving Bevacizumab, early-stage disease (Stages I–III) was associated with superior overall survival relative to Stage IV (p = 0.0004). In contrast, BRAF-mutant tumors with microsatellite-stable (MSS) status displayed poorer prognosis despite higher chemotherapy exposure (OR = 7.226, p < 0.001; p = 0.0000). Among EOCRC patients treated with FOLFOX, RTK-RAS alterations were linked to worse outcomes (p = 0.0262). The system also identified ancestry-enriched noncanonical mutations—including CBL, MAPK3, and NF1—with NF1 mutations significantly associated with improved prognosis (p = 1 × 10⁻⁵). Conclusions: AI-HOPE-RTK-RAS exemplifies a new class of conversational AI platforms tailored to precision oncology, enabling integrative, real-time analysis of clinically and biologically complex questions. Its ability to uncover both canonical and ancestry-specific patterns in RTK-RAS dysregulation—especially in EOCRC and populations with disproportionate health burdens—underscores its utility in advancing equitable, personalized cancer care. This work demonstrates the translational potential of domain-optimized AI tools to accelerate biomarker discovery, support therapeutic stratification, and democratize access to multi-omic analysis. 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

Fibrotic disorders pose a significant global health burden due to limited treatment options, creating an urgent need for novel therapeutic strategies. Amphiregulin (AREG), a low-affinity ligand for the epidermal growth factor receptor (EGFR), has emerged as a key mediator of fibrogenesis through dual signaling pathways. Unlike high-affinity EGFR ligands, AREG induces sustained signaling that activates downstream effectors and promotes the integrin-mediated activation of transforming growth factor (TGF)-β. This enables both canonical and non-canonical EGFR signaling pathways that contribute to fibrosis. Elevated AREG expression correlates with disease severity across multiple organs, including the lungs, kidneys, liver, and heart. The therapeutic targeting of AREG has shown promising antifibrotic and anticancer effects, suggesting a dual-benefit strategy. The increasing recognition of the shared mechanisms between fibrosis and cancer further supports the development of unified treatment approaches. The inhibition of AREG has been shown to sensitize fibrotic tumor microenvironments to chemotherapy, enhancing combination therapy efficacy. Targeted therapies, such as Self-Assembled-Micelle inhibitory RNA (SAMiRNA)-AREG, have demonstrated enhanced specificity and favorable safety profiles in preclinical studies and early clinical trials. Personalized treatment based on AREG expression may improve clinical outcomes, establishing AREG as a promising precision medicine target for both fibrotic and malignant diseases. This review aims to provide a comprehensive understanding of AREG biology and evaluate its therapeutic potential in fibrosis and cancer. Full article

In this perspective, we highlight the relevance of the FA-Hippo signaling pathway and its regulation of the Yes-associated protein (YAP) and the transcriptional coactivator with a PDZ-binding domain (TAZ) as main players in the process of implants integration. The modulation and responses of YAP/TAZ triggered by substrate and ECM stiffness are of particular interest in the construction of materials used for medical implants. YAP/TAZ nuclear localization and activity respond to the substrate stiffness by several mechanisms that involve the canonical and non-canonical Hippo signaling and independently of the Hippo cascade. YAP/TAZ regulate the expression of genes involved in several mechanisms of relevance for implant integration such as the proliferation and differentiation of cell precursors and the immune response to the implant. The influence of substrate stiffness on the regulation of the immune response is not completely understood and the progress in this field can contribute to the designing of an adequate implant design. Though the use of nano-biomaterials has been proved to contribute to implant success, the relationship between grain size and stiffness of the material has not been explored in the biomedical field; filling these gaps in the knowledge of biomaterials will highly contribute to the design of biomaterials that could take advantage of the cells sensing and response to the stiffness at the implant interface. Full article

Galectin-3 (Gal-3) is a β-galactoside-binding lectin that mediates diverse signaling events in multiple cell types, including immune cells. It is also a prognostic indicator for multiple clinically important disorders, including cardiovascular disease. Gal-3 binds to cell surface glycans to form lattices that modulate surface receptor signaling and internalization. However, the tissue-specific regulation of Gal-3 surface expression remains poorly understood. Here, we review evidence for the involvement of Gal-3 in cell surface signaling, intranuclear events, and intracellular trafficking. Our focus will be on the O-GlcNAc modification as a regulator of Gal-3 biosynthesis, non-canonical secretion, and recycling. We argue that the nutrient-driven cytoplasmic hexosamine biosynthetic pathway (HBP) and endomembrane transport mechanisms generate unique pools of nucleotide sugars. The differing levels of nucleotide sugars in the cytosol, endoplasmic reticulum (ER), and Golgi apparatus generate differential thresholds for the responsiveness of O-GlcNAc cycling, N- and O-linked glycan synthesis/branching, and glycolipid synthesis. By regulating Gal-3 synthesis and non-canonical secretion, O-GlcNAc cycling may serve as a nexus constraining Gal-3 cell surface expression and lattice formation. This homeostatic feedback mechanism would be critical under conditions where extensive glycan synthesis and branching in the endomembrane system and on the cell surface are maintained by elevated hexosamine synthesis. Thus, O-GlcNAc cycling and Gal-3 synergize to regulate Gal-3 secretion and influence cellular signaling. In humans, Gal-3 serves as an early-stage prognostic indicator for heart disease, kidney disease, viral infection, autoimmune disease, and neurodegenerative disorders. Since O-GlcNAc cycling has also been linked to these pathologic states, exploring the interconnections between O-GlcNAc cycling and Gal-3 expression and synthesis is likely to emerge as an exciting area of research. 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

Studies have emphasized alleviating fibrogenesis through interference with adenosine signaling in experimental diabetic nephropathy. We found that the in vivo antagonism of the adenosine A_2B receptor (A_2BAR) using MRS1754 in diabetic rats impedes the diabetes-induced glomerular expression of the mesenchymal-like transformation markers Snail and α-SMA, while the loss of the epithelial podocyte-specific proteins nephrin and ZO-1 was prevented. Furthermore, the production of MCP-1, CCL3, TGF-β, and the transcript levels of inflammatory mediators was reduced by A_2BAR antagonism. Using human podocytes in vitro, we demonstrated that A_2BAR antagonism affected the TGF-β-induced activation of SMAD2/-3, as evidenced by the attenuated phosphorylation of SMAD2/-3 and decreased SMAD3 occupancy at target gene promoters following the MRS1754 treatment. Moreover, the non-canonical activation of p65-NF-κB, the primary inflammatory signaling pathway downstream of TGF-β, and the expression of Snail were also reduced by MRS1754. We conclude that an A_2BAR blockade interferes with the pathogenic TGF-β signaling cascade responsible for the phenotypical transformation of podocytes, thereby alleviating diabetic glomerulopathy. Full article

Background/Objectives: Currently, there is limited knowledge on the molecular mechanisms of the “non-canonical” Hippo signaling pathway in hematopoietic tumor cells. We have shown that targeting the MST1/2 kinases, which are the key molecules in this signaling pathway, may be an effective approach to the treatment of hematologic tumors. Methods: The methods used in this study include cell growth assays, caspase assays, Western blot hybridizations, flow cytometry, and whole-transcriptome analyses. These methods allowed us to better understand the molecular pathways at play. Results: Our results showed that XMU-MP-1, an inhibitor of MST1/2 kinase, specifically reduces the viability of hematopoietic cancer cells but not breast cancer cells. It effectively inhibits the growth of the tumor B- and T-cell lines by blocking cell cycle progression, mainly during the G2/M phase, inducing apoptosis and autophagy. XMU-MP-1 treatment led to increased caspase 3/7 activity and increased levels of the cleaved PARP protein. Levels of the LC3-II protein were also shown to be increased, while the level of p62 decreased. These changes are associated with apoptosis and autophagy, respectively. RNA-seq analysis has demonstrated that XMU-MP-1 suppressed the expression of cell cycle regulators, such as E2F, and cell division cycle genes CDC6,7,20,25,45; cyclins A2,B1,B2, and cyclin-dependent kinases. At the same time, it increased the expression of genes involved in apoptosis, autophagy, and necroptosis. Conclusions: Combinations of growth assays, caspase assays, Western blotting, and RNA-seq have shown that the dramatic reduction in the number of hematopoietic tumor cells after treatment with XMU-MP-1 is due to both cytostatic and cytotoxic effects. The use of MST1/2 kinase inhibitors could be highly promising for complex therapy of hematological tumors. Full article