Search Results (1,040)

Cheliped regeneration in the E. sinensis is a tightly regulated physiological process, yet the molecular regulatory mechanisms underlying sexual dimorphism during regeneration remain unclear. In this study, we combined morphological observation with transcriptomic analysis to systematically investigate the regenerative stage characteristics and sex-related differences. The papilla stage 4 dpa was identified as a pivotal transitional stage, bridging initial wound healing and cellular dedifferentiation (2 dpa) with subsequent redifferentiation and morphogenesis (7 dpa). Morphological sex-based differences characterized by larger regenerating chelipeds in males became prominent by the late stage (28 dpa). Notably, the molecular foundation of sexual dimorphism was found to be established at 4 dpa, significantly preceding the emergence of phenotypic differences. This early divergence was driven by sex-dimorphic endocrine networks: males exhibited preferential expression of genes such as Fem-1c-like, Cyp2L1-like, CpAMP1A-like and Nedd4-like, while females showed enrichment in elevated aromatase activity. Weighted gene co-expression network analysis (WGCNA) identified the Hox gene Antp as a core hub regulator, exhibiting high co-expression with key epidermal-related genes such as Cht6, Cht2-like and more. Its suppressed expression at 2 dpa aligned with the requirements for dedifferentiation, whereas its peak at 4 dpa indicated a crucial role in orchestrating appendage patterning and exoskeleton assembly. RNA interference (RNAi) knockdown of Antp resulted in obscured differentiation between the propodus and carpus in both sexes and confirmed its regulatory control over downstream targets including Ubx, Bmp2-like, and CpAMP1A-like. This study suggests a putative hierarchical regulatory model in which systemic hormonal signals may integrate Antp and other sex-biased regulators to potentially facilitate structured limb regeneration. These findings offer tentative novel insights into the interplay between developmental plasticity and sex-based regulatory divergence in decapod crustaceans. Full article

Cognitive impairment in schizophrenia remains insufficiently addressed by existing treatments. Current FDA-approved therapies primarily modulate neurotransmitter systems, resulting in incomplete symptom control and substantial adverse effects. There is therefore a critical need for therapeutic strategies that more directly address the intracellular signaling mechanisms underlying synaptic dysfunction and cognitive deficits in schizophrenia. Protein phosphatases represent an essential but historically underexplored class of signaling enzymes that regulate phosphorylation-dependent control of synaptic receptor trafficking, plasticity, and neuronal circuit function. Although multiple phosphatases have been implicated in schizophrenia through genetic, post-mortem, and functional studies, their therapeutic targeting has been limited by challenges related to selectivity, cellular permeability, and pleiotropy. Here, we review the etiology of schizophrenia and limitations of current pharmacological approaches, synthesize evidence linking specific protein phosphatases to schizophrenia pathophysiology, and discuss emerging strategies, including allosteric modulation and targeted protein degradation, that may enable selective intervention in phosphatase-driven signaling pathways. We highlight the striatal-enriched tyrosine phosphatase STEP (PTPN5) as a case study illustrating how selective phosphatase modulation can restore synaptic signaling in schizophrenia-relevant models. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, driven by aggressive tumor biology, extensive intratumoral heterogeneity, and profound resistance to standard therapies. While recurrent genetic alterations such as KRAS mutations are central to PDAC initiation, growing evidence demonstrates that epigenetic dysregulation is a critical determinant of disease progression, cellular plasticity, immune evasion, and therapeutic failure. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNA regulation, shape transcriptional programs without altering the underlying DNA sequence, rendering them dynamic and potentially reversible therapeutic targets. This review provides a comprehensive overview of key epigenetic proteins implicated in PDAC, encompassing writers, readers, and erasers of chromatin marks. Aberrant activity of histone methyltransferases and acetyltransferases, bromodomain-containing proteins, histone deacetylases, and demethylases orchestrates transcriptional reprogramming that promotes epithelial–mesenchymal transition, stem-like phenotypes, metabolic adaptation, and resistance to chemotherapy and radiotherapy. In parallel, epigenetic alterations within the tumor microenvironment contribute to stromal activation and immune suppression, further limiting therapeutic efficacy. We summarize recent advances in pharmacological targeting of epigenetic regulators and discuss the rationale for combination strategies integrating epigenetic inhibitors with cytotoxic agents, targeted therapies, and immunotherapies. Emphasis is placed on emerging experimental platforms—including patient-derived organoids, co-culture systems, and in vivo models—combined with multi-omic profiling and computational approaches to identify biomarkers of response and optimize therapeutic design. Collectively, this review highlights epigenetic regulation as a central and actionable vulnerability in PDAC and outlines future directions toward biomarker-guided, personalized epigenetic therapies aimed at overcoming resistance and improving clinical outcomes. Full article

Type 1 diabetes (T1D) results from autoimmune-mediated destruction of pancreatic β-cells, leading to insulin deficiency and chronic hyperglycemia. β-cell replacement represents a promising therapeutic strategy, yet the identification of a sustainable and immune-compatible cell source remains a major challenge. Here, we explore the potential of the gastrointestinal (GI) epithelium as an alternative source of β-cells through in vivo cellular reprogramming. Given the large size and highly regenerative nature of the GI tract, partial reprogramming could provide a renewable source of insulin-producing (insulin⁺) cells. We demonstrate that ectopic expression of Pax4 is sufficient to convert gut endocrine L-cells into insulin⁺ cells in vivo. Phenotypic analyses reveal that these gut-derived cells express key β-cell markers, components of the glucose-sensing machinery, and properly process proinsulin into mature insulin. Functional studies using organoids derived from Pax4-expressing gut epithelium further demonstrate that these cells display glucose-responsive insulin secretion. Collectively, our findings highlight the plasticity of gut endocrine cells and support the feasibility of generating β-like cells from the GI epithelium, providing a potential avenue for the development of alternative cell-based therapies for T1D. Full article

Nuclear mechanics and mechanotransduction are involved in the migration and invasion process, such as those in which the cells need to deform themselves to pass through constrictions. Specifically, properties like nuclear softness, viscoelasticity, plasticity (like nuclear pore complexes) and deformability are critical in cancer and its malignant progression. The nucleus represents a physical barrier for the migration and invasion in dense 3D extracellular matrix (ECM) scaffolds. Therefore, the deformability of the nucleus seems to determine the migration limit in circumstances where the enzymatic remodeling of the surroundings is impaired. There are still significant knowledge gaps regarding effects of nuclear deformation during cancer dissemination. It seems that nuclear deformation can alter gene transcription, induce alternative splicing processes, impact nuclear envelope rupture, nuclear pore complex dilatation, damage the DNA, and increase the genomic instability. These mechanically induced alterations can in turn impact the migratory behavior of the cancer cells. The stiffness of the nucleus relies on the condensation of chromatin, and the nuclear lamina, which consists of a network of intermediate filaments underneath the nuclear envelope. All of this is discussed in the review and it is argued that nuclear deformability is universally found in various cancer types. Another focus is placed on the nuclear envelope proteins like emerin, and the SUN-KASH complex and how they contribute to the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex, which consequently couples the nucleus and the cytoskeleton. It is argued that this connection is crucial for force transmission, which governs nuclear stiffness dynamically, depending on the force applied. In this review, recent findings are described that couple ECM-induced nuclear mechanosensing and mechanotransduction with the migration and invasion of cancer cells. Moreover, it is suspected that changes in the mechanosensory characteristics of the cell nucleus could play a pivotal part in the malignancy of cancer cells and the heterogeneity of tumors. Finally, it is discussed what impact the individual elements of the nucleus offer to mechanically alter cellular migration and invasion in cancer and its malignant progression. Full article

Rapid responses to environmental changes are essential for maintaining fitness. In pathogenic fungi such as the dermatophyte Trichophyton interdigitale, appropriate responses to environmental shifts determine successful infection. Transcriptional regulation and alternative splicing (AS) are key modulators of fungal adaptation and pathogenesis. Here, we validated the role of the transcription factor PacC in coordinating AS in T. interdigitale grown in infection-mimicking medium. RNA-seq analysis of a ΔpacC mutant revealed a predominance of intron retention events, mainly involving introns 1 and 2, indicating defective splicing and potential nonsense-mediated decay of genes related to ion transport, metabolism, and genome maintenance. These alterations compromised energy balance, ergosterol biosynthesis, and cellular homeostasis. PacC-dependent AS generated alternative isoforms of cytoskeletal and metabolic proteins, including myosin-1 and a GH3 β-glucosidase, potentially modulating enzymatic activity, metabolic burden, and cell wall remodeling during infection. Exon-skipping in the chromatin remodeler RSC1 suggests PacC involvement in epigenetic regulation under host-mimicking conditions. Transmission electron microscopy revealed possible Woronin bodies, cytoplasmic disruption, and cell wall thinning in the mutant. Overall, PacC integrates transcriptional and post-transcriptional regulation to promote adaptation, survival, and virulence, highlighting AS as a regulatory layer linking environmental sensing to metabolic and epigenetic plasticity in pathogenic fungi. Full article

Embryogenesis is a critical process for which nutritional and metabolic signals act as informational cues that shape adipose tissue development and establish long-lasting metabolic health. Emerging evidence indicates that adipose tissue is not a passive energy storage but a developmentally and metabolically dynamic organ. Cellular composition, functional capacity, and plasticity of adipose are programmed early through coordinated transcriptional, epigenetics, and proteomics processes. Maternal environments in nutritional challenge, including overnutrition and malnutrition, influence adipocyte lineage commitment, depot-specific expansion, and metabolic functionality, predisposing offspring to divergent risks of obesity and metabolic disease. The future of perinatal adipose biology and genomics relies on integrating multi-omics approaches with an artificial intelligence (AI)-driven analytical perspective to resolve complex developmental processes and predict long-lasting metabolic health. Furthermore, the incorporation of sex-specific models is important, which will be essential for capturing biological heterogeneity and ensuring translational relevance. Together, these advance perspectives are predisposed to shift the field from descriptive associations toward predictive and preventive paradigms, reinterpreting metabolic disease risk as a modifiable consequence of early-life adipose programming rather than an inevitable outcome of later-life exposures. Full article

Oral squamous cell carcinoma (OSCC) represents a major global health burden and remains one of the most prevalent and aggressive malignancies of the head and neck region. Despite significant advances in surgical techniques, chemotherapy, and radiotherapy, patient outcomes have improved only modestly over recent decades. The high recurrence rate, metastatic potential, and resistance to therapy underscore the complexity of OSCC biology and the limitations of conventional treatment approaches. In recent years, the concept of cancer stem cells (CSCs) has reshaped the understanding of tumor initiation, progression, and therapeutic failure in OSCC. These cells, characterized by self-renewal capacity and phenotypic plasticity, are believed to sustain tumor growth, drive recurrence, and mediate resistance to therapy. Parallel to this, insights into epigenetic regulation, including DNA methylation, histone modifications, and non-coding RNAs, have revealed new layers of molecular heterogeneity and adaptability in oral carcinogenesis. The integration of CSC biology with epigenetic modulation offers a promising foundation for the development of targeted and personalized therapeutic strategies. Novel approaches aim to eradicate CSCs, induce their differentiation, or reprogram their malignant phenotype through the use of epigenetic inhibitors and molecular modulators. This review summarizes current knowledge on the molecular and cellular mechanisms driving OSCC pathogenesis, highlights the emerging role of CSCs and epigenetic regulators, and discusses the challenges and perspectives of translating these findings into effective clinical therapies. Full article

Deuterium abundance has been proposed as a modulator of cellular metabolism; however, its influence on cancer-associated gene expression networks remains incompletely characterized. We analyzed A549 lung adenocarcinoma cells cultured across four deuterium concentrations (40, 80, 150, and 300 ppm) using NanoString nCounter profiling. Expression data were processed through multistep filtering, symbolic trajectory encoding, and density-based spatial clustering (DBSCAN) to identify extreme expression responders, and Gaussian mixture modeling (GMM-6) to resolve coordinated gene-expression modules. DBSCAN identified 11 outlier genes under deuterium depletion, including reduced expression of multidrug-resistance–associated ABCB1 (−42% at 80 ppm), proliferative signaling component FGFR4 (−19%), and transcriptional amplifier MYCN (−24%). In contrast, enrichment at 300 ppm produced a broad increase in oncogenic expression (mean +44%), with marked elevation of inflammation-related (IL6, TGFBR2) and invasion-associated (MMP9) genes. GMM-6 clustering of the remaining core network resolved six functional modules, indicating that depletion preferentially reduces expression of genes associated with plasticity-related programs (Cluster 5: TGFB1, S100A4), while basal survival-associated genes (Cluster 6: BIRC5, RET) remain comparatively stable. Together, these results indicate that deuterium concentration acts as a bidirectional modulator of gene expression programs in the A549 model, with enrichment broadly elevating oncogenic expression and moderate depletion associated with selective downregulation of genes linked to resistance, signaling, and invasive behavior. Significance: Deuterium depletion is associated with reduced expression of genes involved in multidrug resistance, growth-factor signaling, and transcriptional amplification, revealing deuterium-responsive transcriptional vulnerabilities within the A549 lung adenocarcinoma model. Full article

Lamin A/C is emerging as a promising candidate regulator at the intersection of nuclear mechanics, chromatin organization, and gene regulation, linking structure and regulation, mechanics and epigenetics, constraint and plasticity. Lamin A/C was previously considered a static structural scaffold; however, it is now recognized as a dynamic component of nuclear organization that links physical cues to epigenetic and transcriptional states. Lamin A/C regulates three-dimensional genome structure, constrains chromatin mobility, and influences cell transitions between plastic and committed states through its interactions with heterochromatin at the nuclear periphery and active chromatin domains in the nuclear interior. In cancer, these functions appear to be dependent on the context. Lamin A/C has been implicated in crucial biological processes, including invasion, survival under mechanical stress, lineage plasticity, and therapeutic response. Its prognostic value varies across tumor types. This heterogeneity indicates that lamin A/C does not function as a traditional oncogene or oncosuppressor; instead, it operates as a nuclear rheostat, influencing the behavior and development of tumor cells. This review examines the potential clinical benefits of lamin A/C while considering its implications for normal tissue functions. It aims to improve understanding of cellular adaptability and vulnerability in cancer through the exploration of lamin A/C biology. Full article

Cells adapt their phenotypes in noisy microenvironments while maintaining robust decision-making. We develop a coarse-grained theoretical framework in which cellular phenotypic adaptation is described as Bayesian decision-making coupled to replication and diffusion. This leads to an effective Fokker-Planck equation with an emergent fitness landscape governing phenotypic dynamics. We identify distinct phenotypic regimes homeostatic fixation, bistable decision-making, critical switching, and runaway explosion and propose a biological interpretation in which homeostatic and bistable landscapes correspond to healthy differentiated cell states, whereas explosive landscapes capture stem-like or cancer-like behavior. In the Gaussian setting, the correlation between intrinsic and extrinsic states directly encodes mutual information and acts as a bifurcation parameter: high correlation produces shallow or explosive landscapes associated with phenotypic plasticity, while reduced correlation stabilizes differentiated fates by deepening potential wells. We further show that proliferation reshapes these landscapes in a nontrivial manner. Proliferation conditionally stabilizes local homeostasis without altering global confinement, or cooperates with biased environmental sensing to eliminate homeostasis/bistability and drive cancer-like phenotypic explosion even at high phenotypic fidelity. Finally, we show that negative intrinsic–extrinsic correlations suppress explosive dynamics but also reduce bistable plasticity, suggesting a robustness–plasticity trade-off. Together, our results suggest that development, tissue homeostasis, and carcinogenesis can be understood as information-driven deformations of a Bayesian phenotypic fitness landscape. Full article

“Smart” nanoparticles are often presented as the vanguard of precision cancer therapy, defined by engineered abilities to sense predefined stimuli, enhance targeting, and control therapeutic release. Yet this notion of smartness remains largely material-centric and only partially reflects how nanomedicines behave in vivo. Cells exposed to nanoparticles are not passive recipients of engineered functions; they actively interpret these perturbations through integrated stress-response, metabolic, transcriptional, and innate immune programs. These cell-state trajectories can determine efficacy, tolerance, resistance, or toxicity, and can do so independently of uptake, biodistribution, or triggerable release efficiency. Accordingly, evaluation strategies that prioritize delivery metrics and limited a priori molecular markers may misestimate functional performance and durability. This Perspective proposes a cell-aware reframing in which smartness is defined by biological controllability: the capacity of a nanoparticle system to elicit predictable, mechanistically interpretable, and therapeutically favorable cell-state trajectories across relevant malignant and non-malignant compartments. A practical path forward is to integrate time-resolved functional profiling into benchmarking using compact response signatures that report stress buffering, immune activation or suppression, and the emergence of tolerant states. A practical path forward is to integrate time-resolved functional profiling into benchmarking using compact response signatures that report stress buffering, immune activation or suppression, and the emergence of tolerant states. Here, biological controllability refers to the ability of a nanoparticle system to reproducibly steer integrated cellular stress, metabolic, and immune programs toward predefined therapeutic endpoints while minimizing adaptive escape across heterogeneous compartments. Full article

Maintenance of skeletal muscle mass is essential for mobility, metabolic homeostasis, and clinical outcomes across a wide spectrum of physiological and pathological conditions. While muscle atrophy and hypertrophy have traditionally been interpreted through upstream anabolic–catabolic signaling and proteolytic pathways, accumulating evidence indicates that ribosome biogenesis and translational control represent rate-limiting determinants of muscle plasticity. However, this regulatory layer remains insufficiently integrated into current models of muscle adaptation and disease. In this review, we synthesize recent advances in ribosomal RNA transcription, ribosomal protein dynamics, and translational regulation in skeletal muscle, with particular emphasis on signaling networks governed by mTORC1, c-Myc, AMPK, and FOXO. We highlight ribosome biogenesis as a central hub linking mechanical loading, nutrient availability, inflammatory stress, and metabolic status to protein synthesis capacity. Evidence from human and animal studies demonstrates that impaired ribosome production and translational efficiency precede and predict muscle atrophy in disuse, aging, cancer cachexia, and chronic disease, whereas ribosome expansion is a prerequisite for sustained hypertrophy. Beyond quantitative regulation, we discuss the emerging concept of ribosome heterogeneity as a qualitative layer of translational control that may enable selective mRNA translation during muscle growth, stress adaptation, and degeneration. We further examine ribosome–mitochondria crosstalk as a critical but underexplored mechanism coordinating anabolic capacity with cellular energetics. Finally, we outline therapeutic implications, highlighting exercise, nutritional strategies, and indirect pharmacological interventions that preserve ribosomal competence, and propose ribosome-based biomarkers as promising tools for precision management of muscle-wasting disorders. Collectively, this review positions ribosome biology as a translationally relevant framework bridging molecular mechanisms with therapeutic perspectives in skeletal muscle atrophy and hypertrophy. Full article

Cancer is increasingly recognized as a systems-level disorder characterized not only by genetic alterations but also by persistent dysregulation of stress-adaptive signaling networks integrating inflammation, metabolism, immune modulation, and cellular plasticity. Within this framework, reactive oxygen species (ROS) function as flux-dependent regulators of signaling fidelity rather than merely cytotoxic byproducts. Therapeutic strategies centered on single high-affinity targets or indiscriminate antioxidant suppression often fail to achieve durable responses in redox-heterogeneous and inflammation-driven malignancies. Multi-component herbal formulations represent chemically diverse systems capable of distributed pharmacodynamic modulation across interconnected signaling nodes and heterogeneous pharmacokinetic exposure profiles arising from multi-constituent absorption kinetics. Ojeoksan (Wu Ji San), a classical East Asian multi-herbal decoction, has accumulated experimental and clinical evidence demonstrating regulatory effects on inflammatory mediators, metabolic homeostasis, mitochondrial stress responses, and immune signaling pathways. Rather than inducing abrupt pathway inhibition, OJS appears to exert graded, parallel modulation across multiple redox-sensitive axes. Here, we reinterpret OJS within a flux-based pharmacological framework, conceptualizing it as a distributed redox-buffering architecture rather than a direct cytotoxic agent. By integrating Korean and Chinese research traditions with systems-level redox modeling and electrochemical perspectives, we propose that multi-component formulations may enhance pharmacodynamic robustness through controlled modulation of ROS amplitude and multi-node buffering while temporally distributing pharmacodynamic signals through multi-component pharmacokinetic synchronization. From a formulation science standpoint, such distributed electrochemical diversity may expand therapeutic tolerance windows and mitigate compensatory pathway escape in chronic inflammatory and therapy-resistant cancers. This perspective supports repositioning multi-herbal formulations as network-aligned pharmacological systems compatible with modern molecular pharmacology formulation-level design principles and rational combination therapy strategies. Full article

Synthetic or plastic microfibers (MFs) are an emerging form of microplastic pollution in marine ecosystems, derived from textile degradation and weathering of fishing and aquaculture gear. Despite extensive evidence of MFs in marine organisms, the effects of MFs exposure on mussels remain poorly understood. This study investigated the impact of synthetic MFs on the mussel Mytilus galloprovincialis (Lamarck, 1819) over a semi-chronic time scale of 14 days, using MFs produced by grinding a microfiber cloth. Adult mussels were exposed to three MFs treatments: 8, 40, and 100 MFs/L, reflecting current and future scenarios in the Black Sea. Biomarkers assessed included lysosomal membrane stability (LMS), catalase (CAT), glutathione-S-transferase (GST), and acetylcholinesterase (AChE) activities. Significant lysosomal membrane destabilization (p < 0.05) occurred across all treatments. CAT activity in the digestive gland significantly decreased by 31.2%, 53.3%, and 62.1% at 8, 40, and 100 MFs/L, respectively. GST activity showed inhibition at 8 and 100 MFs/L and stimulation at 40 MFs/L. AChE activity decreased at 8 MFs/L but increased at higher concentrations. These results indicate that even environmentally relevant levels of synthetic MFs can alter cellular stability and enzymatic responses in mussels, suggesting potential ecological risks for marine bivalves. Full article