Search Results (444)

The zinc finger protein 36 (ZFP36) family, including ZFP36/tristetraprolin (TTP), ZFP36 CCCH-type-like 1 (ZFP36L1), and ZFP36 CCCH-type-like 2 (ZFP36L2), consists of conserved CCCH-type tandem zinc-finger RNA-binding proteins. These proteins recognize AU-rich elements (AREs) in target mRNAs and promote deadenylation, decay, and translational repression. In this review, we use the term post-transcriptional immune checkpoint in a restricted conceptual sense: ZFP36 family proteins are intracellular, RNA-level negative regulators that tune the magnitude, duration, and resolution of immune effector programs, rather than classical receptor-ligand immune checkpoints such as programmed cell death protein 1 (PD-1)/ programmed death-ligand 1 (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). We summarize structural features, ARE-recognition mechanisms, mRNA decay pathways, translational repression mechanisms, and post-translational regulation of the ZFP36 family, while explicitly distinguishing mechanisms established for ZFP36 from those inferred for ZFP36L1 and ZFP36L2. We then review cell-type-specific roles in innate and adaptive immunity, including myeloid inflammatory responses, barrier tissue inflammation, innate lymphoid cell function, T cell activation and effector differentiation, regulatory T cell stability, B cell development, and antiviral immunity. In cancer, ZFP36 family members show context-dependent functions that should be separated into tumor-cell-intrinsic effects and immune-microenvironment-dependent effects. They suppress tumor progression by destabilizing pro-inflammatory, angiogenic, metabolic, and epithelial–mesenchymal transition (EMT)-associated transcripts, yet may also restrict antitumor immune responses or promote immune evasion in selected tumor contexts. Finally, we discuss autoimmune and inflammatory diseases, allergic disorders, transplant immunity, neuroimmune relevance, and therapeutic strategies, emphasizing the current evidentiary limits, preclinical status, and safety concerns of ZFP36 family modulation. Full article

Influenza viruses are a major global health threat because of their recurring seasonal burden and continuing pandemic potential. Central to the viral life cycle is the viral ribonucleoprotein complex (vRNP), the functional unit of the segmented genome, in which each negative-sense RNA segment is encapsidated by oligomeric nucleoprotein (NP) and bound at its termini by the polymerase complex (FluPol). Recent advances in structural biology have revealed high-resolution structures of FluPol in distinct conformations, NP-RNA helical assemblies, and intact vRNP architectures, providing a structural framework for understanding vRNP assembly, polymerase conformational switching, and RNA synthesis in the RNP context. By contrast, current models for vRNP trafficking and selective genome packaging still rely largely on virological, biochemical, and cell biological evidence, with only limited structural resolution. In this review, we synthesize current knowledge of vRNP assembly, transcription, replication, intracellular trafficking, and selective genome packaging, and discuss the major unresolved questions in each area as well as their implications for antiviral development. Full article

Tea tree essential oil (TTO), extracted from Melaleuca alternifolia, is a terpene-rich botanical antimicrobial with demonstrated broad-spectrum activity against foodborne pathogens and spoilage microorganisms. Its bioactivity is principally attributed to oxygenated monoterpenes, most notably including terpinen-4-ol, γ-terpinene, and α-terpinene, whose structure–activity relationships govern interactions with microbial membranes and intracellular targets. This review provides a comprehensive, mechanistically grounded analysis of TTO as a sustainable antimicrobial platform for food preservation applications. The physicochemical determinants of TTO performance are critically assessed, encompassing chemotype-dependent compositional variability, hydrophobicity, limited aqueous solubility, and oxidative instability, with emphasis on how these properties constrain efficacy in complex food matrices. Antimicrobial mechanisms are systematically examined, including membrane permeabilization, disruption of cellular homeostasis, oxidative stress induction, and quorum-sensing interference. Focus is placed on nanostructured delivery systems, including nanoemulsions, biopolymer-based encapsulants, and hybrid nanocomposites, that improve physicochemical stability, modulate release kinetics, and potentiate antimicrobial activity. The integration of these engineered formulations into edible coatings, active packaging, and sanitation protocols across fresh produce, meat, and dairy systems is evaluated in the context of practical food safety applications. Translational limitations are addressed, including volatility, sensory incompatibility, regulatory constraints, and concentration-dependent cytotoxicity considerations. Collectively, this review positions TTO-based nanoformulations as a scientifically promising and technologically scalable approach to next-generation food preservation, while identifying critical gaps that must be resolved to support regulatory acceptance and commercial implementation. Full article

Human spaceflight in microgravity induces profound physiological adaptations, yet its effects on the sensory system remain comparatively underexplored. While musculoskeletal and cardiovascular changes are well documented, sensory alterations pose equally important challenges to astronaut safety, performance, and post-mission recovery. Calcium ions (Ca²⁺), as universal intracellular messengers, play central roles in sensory transduction, neurotransmitter release, and adaptive signaling across all sensory modalities. Emerging evidence suggests that microgravity may influence Ca²⁺ homeostasis and Ca²⁺-dependent cellular processes, potentially affecting the functional integrity of sensory pathways. In this review, we synthesize current findings on the impact of microgravity on Ca²⁺-dependent processes in the five classical senses. Evidence from spaceflight studies, ground-based analogs, and related physiological models suggests possible alterations in taste receptor signaling, Ca²⁺-binding protein expression, mechanotransduction pathways, and vestibular function. However, direct evidence for microgravity-induced disruption of Ca²⁺ signaling remains limited for several sensory modalities. Collectively, these changes are associated with altered taste and smell perception, visual disturbances, reduced tactile sensitivity, and vestibular imbalance. By integrating both direct evidence and mechanistic hypotheses across sensory systems, this review highlights Ca²⁺ signaling as a potential unifying mechanism underlying sensory adaptation to microgravity. We further identify key knowledge gaps and discuss potential directions for developing targeted countermeasures aimed at preserving sensory function during long-duration missions. Beyond spaceflight, these insights contribute to a broader understanding of Ca²⁺-mediated sensory physiology under extreme environmental conditions. Full article

Virus infection requires coordinated activation of pathogen-sensing, innate immune, and cellular stress response pathways to mount an effective antiviral defense. Recognition of nucleic acid pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) initiates signaling cascades that drive the production of type I interferons (IFNs) and proinflammatory cytokines. These responses are often accompanied by the activation of integrated stress response pathways that help optimize host defense. Cytosolic double-stranded dsDNA, generated during viral infection or released from damaged mitochondria, is sensed by cyclic GMP-AMP synthase (cGAS), which generates 2′3′-cGAMP to activate stimulator of interferon genes (STING). Activated STING translocates from the endoplasmic reticulum to the Golgi, where it drives TBK1-dependent IFN and cytokine production. Previous reports show that cGAS activity is enhanced by Ras-GAP SH3 domain binding protein 1 (G3BP1), a key nucleator of stress granules (SGs), independent of its role in SG assembly. Here, we identify a non-canonical role of G3BP1 as a regulator of DNA sensing responses at multiple levels, including STING intracellular trafficking, in addition to potentiating cGAS activity. Loss of G3BP1 impaired STING-dependent IFN and cytokine responses to HSV-1 infection and viral DNA. G3BP1-deficient cells showed reduced cGAMP-induced STING translocation to the Golgi, induction of type I IFN and proinflammatory cytokines, and activation of the ER stress kinase PERK and stress granule formation. Together, these findings demonstrate G3BP1-STING as a node linking DNA sensing, innate immunity, and stress signaling with broad implications for antiviral defense and diseases characterized by aberrant DNA sensing and stress responses, including neurodegeneration, fibrosis, and autoimmunity. Full article

The MarR family regulators, widespread in bacteria and archaea, control diverse cellular processes, yet the regulatory mode and molecular signaling mechanism remain unclear in Corynebacterium glutamicum. Here, we functionally characterize AesR (aromatic compounds and environmental stimuli-sensing regulator), a MarR-type transcriptional regulator encoded by ncgl0019 in C. glutamicum. RNA sequencing (RNA-seq) analysis of an aesR-deleted strain (ΔaesR) revealed the down-regulation of genes involved in aromatic compounds degradation, stress response, antibiotic resistance and cell envelope biogenesis, correlating with heightened sensitivity of ΔaesR to adverse conditions. RNA-seq, quantitative reverse transcription-PCR (qRT-PCR) and promoter activity analysis uncovered that AesR represses its own operon (including the Zn-dependent protease with chaperone function gene ncgl0020) and the divergent cytochrome C biosynthesis operon ncgl0018-ncgl0017. AesR binds as a dimer to two side-by-side inverted repeats [5′-ACTATG-N₃-CATAGTCGACTA-N₇-TAGTTG-3′] in the ncgl0018-aesR intergenic region with different affinity, and Cu²⁺/Ni²⁺/Zn²⁺ disrupted binding. These metal ions, along with aromatic compounds, organic peroxides, and bactericidal antibiotics, induce both operons in vivo. Notably, penicillin elevates intracellular Cu²⁺/Ni²⁺/Zn²⁺ levels. Collectively, our findings identify AesR as a novel regulator that senses metal ions as direct signals, relieving autorepression and enabling bacterial defense against aromatic compounds and environmental stressors. Full article

Glioblastoma (GBM) remains the most lethal primary brain tumor in adults, with a median overall survival of approximately 15–20 months despite multimodal treatment including surgery, chemoradiation, and Tumor Treating Fields (TTFields). While the survival benefit of TTFields was established by the EF-14 phase III trial, their biological effects extend well beyond the canonical anti-mitotic mechanism and encompass extensive interactions with the GBM tumor microenvironment (TME). This review provides an integrated mechanistic analysis of TTFields–TME interactions in GBM, with a distinctive focus on their convergence with radiotherapy. We examine how TTFields activate innate immune sensing through cGAS/STING and AIM2 inflammasome pathways, drive immunogenic cell death, reprogram tumor-associated macrophages, and prime adaptive T cell responses. We further address TTFields effects on glioma stem cells, blood–brain barrier permeability, and intracellular signaling governing invasion, angiogenesis, and autophagy. Critically, we develop the mechanistic and clinical case for TTFields-radiotherapy combinations, highlighting convergent mechanisms of DNA repair impairment, mitotic catastrophe, and innate immune activation. Practical considerations for concurrent clinical implementation are discussed alongside a research agenda centered on optimal timing, hypofractionation, and predictive biomarkers. Available evidence—largely preclinical—suggests that TTFields may act as a TME-remodeling platform whose potential is most likely to be realized through mechanistically informed combinations. Full article

Toll-like receptors (TLRs) are essential components of the innate immune system that enable host cells to sense microbial and endogenous danger signals and to initiate inflammatory and antimicrobial responses. Activation of TLRs triggers complex intracellular signaling networks that culminate in the induction of pro-inflammatory cytokines, type I interferons, and co-stimulatory molecules. In addition to the well-characterized nuclear factor κB (NF-κB) and interferon regulatory factor (IRF) pathways, mitogen-activated protein kinases (MAPKs) play a critical modulatory role in TLR signaling. MAPK/ERK kinase (MEK) inhibitors were originally developed for the treatment of cancer and are widely used in clinical oncology. Accumulating evidence indicates that pharmacological inhibition of MEK/extracellular signal regulated kinase (ERK) signaling profoundly affects immune cell function and TLR-driven responses. Depending on timing, dose, and disease context, MEK inhibition can attenuate excessive inflammation but may also interfere with protective host defense mechanisms. This duality highlights the context-dependent role of MEK/ERK signaling in infection and inflammation. In this review, I summarize current knowledge on the integration of MEK/ERK signaling into TLR-mediated innate immune responses and discuss the immunological consequences of MEK inhibition in infectious and inflammatory settings. By synthesizing mechanistic and translational studies, I aim to provide a framework for understanding MEK inhibitors as immune modulators rather than as broadly acting anti-inflammatory agents. Full article

Copper ions (Cu²⁺) and intracellular biothiols are tightly coupled in cellular redox regulation, where copper–thiol coordination governs oxidative stress and metal homeostasis. However, analytical platforms capable of sequentially monitoring Cu²⁺ and biothiols within a single molecular system remain scarce. Herein, we report a coumarin-based fluorescent probe XDP that enables sequential ON–OFF–ON sensing of Cu²⁺ and biothiols through a coordination–competition mechanism. The imine (C=N) site of XDP selectively coordinates Cu²⁺, leading to fluorescence quenching arising from coordination-induced electronic perturbation and enhanced nonradiative decay. The probe exhibits a linear response toward Cu²⁺ over 1–80 μM with a detection limit of 0.108 μM. Subsequent competitive binding of biothiols (GSH, Cys, and Hcy) releases Cu²⁺ from the complex, thereby restoring fluorescence and enabling detection within 1–30 μM with submicromolar sensitivity. XDP also displays a large Stokes shift (135 nm), which minimizes spectral overlap and improves signal reliability. Notably, Cu²⁺ binding triggers a distinct color change that supports naked-eye detection and smartphone-based RGB quantification. The probe further enables visualization of Cu²⁺ and thiol-triggered signal recovery in living cells and zebrafish. This work establishes a versatile analytical platform for probing copper–thiol interactions in environmental and biological systems. Full article

Cervical cancer is a common gynecological malignancy, with a 5-year survival rate of only 17% for recurrent or metastatic cases. Increased extracellular matrix stiffness, a key change in the tumor mechanical microenvironment, promotes tumor metastasis via mechanotransduction. Piezo1, a mechanosensitive cation channel, senses matrix stiffness and converts mechanical signals into intracellular chemical signals. Neutrophil extracellular traps (NETs) are overformed in tumors, but the mechanism by which matrix stiffness regulates NETs in cervical cancer remains unclear. We detected matrix stiffness and related protein expression in cervical cancer tissues using atomic force microscopy and histochemical staining. Polyacrylamide gel models were used to culture HeLa/SiHa cells, with transcriptome sequencing and ELISA to analyze IL-8 expression. NETs were induced from human peripheral blood neutrophils, and their effect on lymphatic endothelial cells was evaluated. A TC-1 mouse model was used to verify in vivo effects, and Western blot/ELISA explored the Piezo1/NF-κB pathway. Higher Young’s modulus, increased α-SMA/Collagen I expression and collagen content in metastatic cervical cancer tissues. High matrix stiffness activated Piezo1/NF-κB, upregulated IL-8, induced NETs, and enhanced lymphatic endothelial cell tube formation/migration. BAPN reduced tumor stiffness, inhibited metastasis, and decreased NETs in mice. Knocking down Piezo1 blocked NF-κB activation and IL-8 upregulation. High matrix stiffness activates Piezo1/NF-κB to promote IL-8 secretion and NETs formation, enhancing lymphangiogenesis and cervical cancer metastasis, providing a new target for advanced cervical cancer treatment. Full article

Genetically encoded voltage indicators (GEVIs) have long promised optical access to membrane potential, yet their adoption has lagged significantly behind genetically encoded calcium indicators. A central but underappreciated reason is that the metrics used to evaluate and compare GEVIs—fractional fluorescence change (ΔF/F), kinetics, and signal-to-noise ratio—rest on an assumption that is frequently violated: that GEVI fluorescence reflects a single underlying process. In this perspective, we argue that GEVI signals are composite optical measurements, arising from the superposition of voltage-dependent fluorescence, intracellular and nonresponsive signal, background, and contributions from neighboring cells. Under these conditions, ΔF/F is not a measure of sensor sensitivity but a contrast metric whose value depends on baseline fluorescence composition, optical sampling, and imaging configuration. This reinterpretation has two key consequences. First, it explains a substantial source of variability in GEVI performance that is currently attributed to noise or experimental inconsistency. Second, and more importantly, it reveals that the complexity of GEVI signals is not a limitation to be minimized but a resource to be exploited. By resolving composite signal components, GEVIs can report multiplexed physiological variables, expose hidden conformational states of voltage-sensing domains, probe membrane organization, and reveal intracellular and intercellular electrical coupling. We propose that realizing the full potential of GEVIs requires treating ΔF/F not as a gold standard for sensor performance, but as one interpretable component of a richer optical measurement whose structure encodes multiple layers of cellular physiology. Full article

Chronic and infected wounds remain difficult to treat due to persistent microbial burden, biofilm formation, and dysregulated inflammation. As a multifunctional polyphenol, curcumin exhibits broad-spectrum antimicrobial, anti-inflammatory, and antioxidant activities. Nevertheless, the clinical application of curcumin is constrained by its limited solubility in water, inherent instability, and insufficient bioavailability. Chitosan, a cationic polysaccharide, provides complementary advantages including intrinsic antimicrobial activity, mucoadhesion, and the capacity to form versatile delivery platforms such as nanoparticles, hydrogels, and films. This review reframes chitosan–curcumin systems as dual-function bioactive platforms in which both the carrier and payload actively contribute to therapeutic outcomes. Mechanistically, chitosan disrupts microbial membranes, enhances bioadhesion, and supports tissue regeneration, while curcumin modulates intracellular targets including reactive oxygen species, quorum sensing, and inflammatory signaling pathways. Their integration enables multimodal antimicrobial activity, improved biofilm disruption, and coordinated regulation of the wound-healing cascade. This review critically examines the structure–function relationships governing release kinetics, stability, and cytocompatibility, with particular emphasis on chitosan molecular weight, degree of deacetylation, crosslinking strategies, and curcumin loading. Solubility-enhancement strategies for curcumin, including surfactants, nanoparticles, solid dispersions, and chemical derivatives, are evaluated in the context of antimicrobial efficacy and cytotoxicity. Finally, the review highlights translational challenges and future directions, such as antibiotic synergy, antifungal applications, formulation complexity, and the emerging role of artificial intelligence in predictive material design. Collectively, these insights establish design principles for next-generation multifunctional biomaterials that integrate antimicrobial activity with immune modulation and tissue repair. Full article

L-asparaginase (ASNase) is a paradigmatic amino-acid depletion therapy that induces systemic asparagine starvation and remains foundational in acute lymphoblastic leukemia (ALL). Amino-acid metabolism constitutes a fundamental therapeutic vulnerability in hematologic malignancies, yet the determinants of response to systemic asparagine depletion remain incompletely defined. Asparagine synthetase (ASNS) regulates intracellular asparagine biosynthesis and functions as a stress-responsive metabolic node embedded within adaptive nutrient-sensing pathways. Emerging transcriptomic and proteomic evidence demonstrates that reduced ASNS expression is enriched in biologically distinct subsets of acute myeloid leukemia (AML), particularly those characterized by immature differentiation states and cytogenetic features associated with metabolic fragility, including inv(16) and chromosome 7-associated disease. Clinical experience in natural killer/T-cell (NK/T-cell) neoplasms provides proof-of-principle that enzymatic asparagine depletion can achieve durable therapeutic efficacy in tumors intrinsically dependent on extracellular amino-acid supply, establishing extranodal NK/T-cell lymphoma (ENKTL) as a mechanistically aligned anchor indication beyond acute lymphoblastic leukemia. Integrative molecular analyses further indicate that ASNS deficiency functions as a permissive rather than deterministic biomarker, with therapeutic response modulated by lineage-specific metabolic wiring, adaptive stress signaling, and microenvironmental nutrient buffering. Advances in protein-anchored diagnostic platforms, including intracellular flow cytometry and quantitative proteomics, now enable operationalization of ASNS as a clinically actionable stratification marker. Mechanistic studies also suggest that amino-acid depletion may interact with apoptotic signaling networks, supporting rational combination strategies with targeted agents such as BCL-2 inhibitors. Collectively, these findings support a conceptual framework in which ASNS-low defines a context-dependent metabolic vulnerability rather than a uniform disease-wide predictor, underscoring the need for prospective biomarker-enriched clinical trials to establish ASNS-guided amino-acid depletion as a precision oncology strategy across heterogeneous myeloid and lymphoid malignancies. Full article

Autophagy, also referred to as the “self-eating machinery”, is a crucial process where organisms maintain intracellular homeostasis through recycling or degrading non-essential and damaged cellular components. It is important in numerous biological functions such as cellular differentiation, aging, nutrient sensing, stress response, tissue homeostasis, immunity, and programmed cell death. Autophagy induction occurs with the formation of a double-layered membrane structure called “autophagosome”. The autophagosome wraps damaged organelles or proteins and transports them to the vacuole or lysosome for degradation. Autophagy is beneficial to organisms, and it should be optimally regulated because elevated or decreased levels are detrimental for survival. To date, more than 40 autophagy-related genes (ATGs) have been identified in the budding yeast Saccharomyces cerevisiae, with most having homologs in fungi and higher eukaryotes. Majority of the ATGs in industrial and pathogenic fungal species have been characterized and known to play vital roles in growth, development, and virulence. In this review we provide a comprehensive overview of ATGs in various fungal species and highlight how autophagy is regulated and controls various functions in plant, human, and industrial fungal species. Full article

Adenosine has emerged as a central metabolic signal linking cellular stress to systemic physiological adaptation. Under conditions such as hypoxia, ischemia, inflammation, and tissue injury, extracellular adenosine triphosphate (eATP) released from stressed cells is sequentially metabolized by the ectonucleotidases CD39 and CD73, generating adenosine that accumulates in the extracellular microenvironment. This stress-responsive nucleoside activates four G-protein-coupled receptors (A1, A2A, A2B, and A3), triggering intracellular signaling networks including the cyclic adenosine monophosphate–protein kinase A (cAMP–PKA), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase–protein kinase B (PI3K–Akt), and hypoxia-inducible factor-1 alpha (HIF-1α) pathways. Through these integrated mechanisms, adenosine orchestrates diverse physiological processes such as vascular regulation, metabolic adaptation, immune modulation, and cellular survival. In the cardiovascular system, adenosine promotes coronary vasodilation and ischemic preconditioning, limiting reperfusion injury. In pulmonary tissues, it mediates acute anti-inflammatory responses but may also drive chronic fibrotic remodeling. Within the central nervous system, adenosine functions as a neuromodulator regulating neuronal excitability, sleep–wake homeostasis, and neuroprotection. In the tumor microenvironment, hypoxia-driven adenosine accumulation suppresses cytotoxic T cell and natural killer activity, facilitating immune evasion and tumor progression. Collectively, adenosine signaling represents a central integrative network that links metabolic stress sensing to coordinated cellular adaptation while simultaneously emerging as a clinically actionable therapeutic target across cardiovascular, inflammatory, neurological, and oncological diseases. Full article