Search Results (773)

Osteoarthritis (OA) is a multifactorial degenerative joint disease in which aberrant mechanical cues act in concert with metabolic dysregulation and chronic low-grade inflammation, with chondrocyte hypertrophy representing a key pathological event driving cartilage degeneration. Alterations in extracellular matrix (ECM) properties—including mechanical loading, stiffness and viscoelasticity, topological organization, and surface chemistry—regulate hypertrophic differentiation and matrix degradation in a zone-, stage-, and scale-dependent manner. Microscale measurements often reveal localized stiffening in superficial zones during early OA, whereas bulk tissue testing can show softening or heterogeneous changes in deeper zones or advanced stages, highlighting the context-dependent nature of ECM mechanics. These biophysical signals are sensed by integrin-based adhesion complexes, primary cilia, mechanosensitive ion channels (TRP/Piezo), and the actin cytoskeleton–nucleus continuum, and are transduced into intracellular pathways with zone- and stage-specific effects, governing chondrocyte fate under physiological and osteoarthritic conditions. Mechanism-based anti-hypertrophic strategies include biomimetic scaffold design for focal defects, dynamic mechanical stimulation targeting early OA, and multimodal approaches integrating mechanical cues with biochemical factors, gene modulation, drug delivery, or cell-based therapies. Collectively, this review provides an integrated mechanobiological framework for understanding cartilage degeneration and highlights emerging opportunities for disease-modifying interventions targeting chondrocyte hypertrophy. Full article

Cell fate determination depends on precise and timely control of gene expression programs governed by enhancers, which act as central regulatory elements within chromatin landscapes. Recent studies reveal that enhancers occupy distinct functional states, including poised, primed, and active configurations, and that these states dynamically transition during lineage specification. These transitions, in turn, coordinate chromatin accessibility and transcriptional competence, establishing when and how developmental genes become activated. Beyond individual enhancers, some fate-defining loci employ modular and shadow enhancer architectures that cooperatively regulate transcriptional dose, maintain threshold stability, and buffer developmental programs against stochastic and environmental variation. Comparative analyses across neural, cardiac, and hematopoietic systems illustrate how these enhancer modules are selectively deployed to achieve lineage-specific precision and robustness. Furthermore, enhancer timing, persistence, and quantitative thresholds collectively encode developmental tempo and stability, ensuring faithful progression of cell fate transitions. By considering molecular state transitions together with cooperative enhancer architecture, this review organizes current views on how enhancers may help translate transient cues into stable lineage outcomes, thereby linking chromatin dynamics to developmental precision. Full article

Cells sense and transmit mechanical forces exerted by their environment to the nucleus via adhesion sites and the cytoskeleton. The nucleus interprets these mechanical inputs and determines cell fate and behavior by regulating gene expression. This review addresses how force-generated signals at the cell–extracellular matrix (ECM) interface influence adhesion, signaling, nuclear function, and tissue remodeling. Disruption of these mechanotransduction pathways contributes to the development of diseases such as cancer, fibrosis, and cardiovascular disorders. Advances in technologies that enable the investigation of the underlying mechanisms will support the development of novel treatment strategies for such diseases. Full article

RNA-binding proteins (RBPs) play a pivotal role in post-transcriptional gene regulation, influencing various cellular processes, including development, differentiation, and disease progression. Emerging evidence suggests that RBPs function as critical modulators of the canonical Wnt signaling pathway, a key regulator of cell fate determination, proliferation, and tumorigenesis. By controlling the stability, localization, and translation of Wnt pathway components, RBPs fine-tune the dynamic signaling responses necessary for maintaining cellular homeostasis. Several RBPs have been identified as direct regulators of key components in the Wnt cascade, such as IGF2BP1, HuR, and MSI1, impacting their expression and activity. Dysregulation of these RBPs has been linked to aberrant Wnt signaling, contributing to various pathological conditions such as cancers or developmental disorders. This review explores the emerging landscape of RBPs in the regulation of canonical Wnt signaling, highlighting their molecular mechanism, functional implications, and potential as therapeutic targets in Wnt-driven disease. Full article

Neuroblastoma (NB), a pediatric cancer of sympatho-adrenal (SA) lineage, is marked by disrupted differentiation and cellular heterogeneity. INSM1, a zinc-finger transcription factor, is highly expressed in NB and developing SA tissues, where it regulates neuroendocrine differentiation, especially in chromaffin cells. We investigated INSM1’s role in maintaining an undifferentiated, progenitor-like state in NB and its regulation via metabolic and epigenetic mechanisms. Transcriptomic profiling, promoter assays, and metabolic flux analysis revealed that INSM1 expression correlates with methionine cycle activity, particularly the S-adenosylmethionine (SAM)/S-adenosylhomocysteine (SAH) ratio. Disruption of SAM/SAH balance altered INSM1 promoter activity and histone methylation, implicating epigenetic control in NB cell fate. Retinoic acid-induced differentiation downregulated INSM1 and N-Myc, linking INSM1 to tumor cell immaturity. INSM1 overexpression in SH-SY-5Y cells upregulated neuroendocrine and thyroid hormone-related genes (CHGA, CHGB, DDC, NCAM1, DIO3, TH), while suppressing genes involved in cell cycle (RRM, CDC25A), methionine metabolism (AHCY, MAT2A), transcriptional regulation (MYBL2, EZH2), and oncogenic signaling (ALK, LINC011667). These findings suggest that INSM1 promotes NB aggressiveness by sustaining a neuroendocrine progenitor-like phenotype through metabolic-epigenetic coupling. Full article

Background: Endometriosis is a chronic inflammatory disorder that affects approximately 10% of women of reproductive age and exhibits tumor-like characteristics such as invasion, recurrence, and hormone-dependent proliferation despite its benign nature. Its pathogenesis is thought to involve hormonal imbalance, oxidative stress, hypoxia, immune dysregulation, and epigenetic alterations. This review summarizes how these factors contribute to lesion formation through intracellular signaling pathways, with a particular focus on the role of the stress-responsive transcription factor Forkhead box O (FOXO1). Methods: A comprehensive literature search was conducted using PubMed and Google Scholar without temporal restriction. Results: FOXO1 is a transcription factor that integratively regulates decidualization, cellular senescence, autophagy, and apoptosis. In the normal endometrium, under mild stress or hormonal stimulation, FOXO1 induces decidualization-associated genes (PRL, IGFBP1) and antioxidant enzymes, thereby promoting differentiation and survival. In contrast, in endometriosis, activation of the PI3K/AKT signaling pathway and an estrogen-dominant environment suppress the nuclear activity of FOXO1, leading to apoptosis resistance, accumulation of senescent cells, and chronic inflammation through the senescence-associated secretory phenotype (SASP). Moreover, depending on the intensity and duration of oxidative, metabolic, and environmental stress, FOXO1 drives distinct cellular fates—including decidualization, senescence, and apoptosis—thus contributing to the persistence and progression of endometriotic lesions. Conclusion: Dysregulation of the FOXO1-dependent cellular fate–control network plays a central role in the development of endometriosis. Elucidating the molecular mechanisms governing FOXO1 activity and its nuclear dynamics will be crucial for a comprehensive understanding of disease progression and for the development of novel therapeutic strategies. Full article

Stem cell fate is governed by complex transcriptional networks and dynamic chromatin architectures, with RNA molecules acting as critical regulators. Traditionally, small RNAs have been associated with gene silencing; however, growing evidence reveals that certain RNA species can also activate transcription, a phenomenon termed RNA activation (RNAa). This evolutionarily conserved mechanism functions through both synthetic small activating RNAs (saRNAs) and endogenous RNA molecules, including promoter-targeting microRNAs, small modulatory double-stranded RNAs, and circular RNAs. By modulating chromatin accessibility and engaging the transcriptional machinery, these RNAs orchestrate gene expression programs that control pluripotency maintenance and lineage-specific differentiation in stem cells. This review integrates emerging mechanistic insights and functional evidence to provide a comprehensive perspective on RNAa-mediated gene activation in stem cell biology and highlights its potential as a precise tool for controlling cell fate through epigenetic modulation. Full article

The role of LAP proteins expressed in skeletal muscles (ERBIN, LANO, and SCRIBBLE) and at neuromuscular junctions (NMJs) remains largely unknown. Our previous data demonstrate that LAP proteins are differentially expressed in muscle cells, nerve endings, and terminal Schwann cells, though they are all expressed in myofibers and accumulate at NMJs. ERBIN and SCRIBBLE align with acetylcholine receptor clusters (CHRNs) at the NMJ. In vivo ablation of Erbin is associated with smaller CHRN and upregulation of Lano and Scribble. However, SCRIBBLE was also shown to influence the fate decision of muscle stem cells. Here, we investigated how the absence of SCRIBBLE in skeletal muscle cells might impair skeletal muscle fibers or NMJs. Although conditional Scribble knockout mice did not exhibit changes in weight or viability, force per weight decreased slightly. This was supported by compromised neuromuscular transmission and increased NMJ fragmentation. Moreover, Scribble knockout muscles transcribe less myosin heavy chain genes. Here, we also showed that RAB5, an effector of endocytic recycling, interacts with all LAP proteins, but in Scribble knockout muscles, reduced interaction was detected with ERBIN and LANO. These data suggest that a delicate signaling network employing LAP proteins is necessary for skeletal muscle fibers and NMJs. Full article

Floral induction in late-maturing litchi is vulnerable to warm, humid winters with insufficient chilling. The late cultivar ‘Ziniangxi’ was evaluated during January–February 2024 in an experimental orchard in Hainan, China, when chilling accumulation was very low, with only seven days having a mean air temperature ≤ 15 °C. Under this marginal-chill context, the effects of plant growth regulator (PGR) applications on bud fate were assessed using six single-agent and thirteen composite PGR–nutrient treatments plus a water control, applied as four foliar sprays during floral induction. In the untreated control, the final flowering proportion of tagged shoots was 0.33 in the single-agent trial and 0.05 in the composite trial. In contrast, ABA (3.33 mg L⁻¹) increased flowering to 0.53, and ethephon- or brassinolide-based applications to 0.40–0.47. The most effective composite formulations raised flowering further to 0.50–0.63. These composite applications also increased leaf starch from about 4 mg g⁻¹ FW in the control to approximately 8–9 mg g⁻¹ FW ($p<0.05$), whereas sucrose concentrations showed only small differences among treatments. Across trials, shoots that became floral consistently exhibited higher leaf starch than vegetative shoots. Gene-expression analyses indicated that floral buds had higher transcript abundance of LcFUL and lower transcript levels of LcFLC and other floral repressors than vegetative buds, consistent with their assignment to floral versus vegetative categories. Overall, the results suggest that appropriately timed ethephon–ABA-based PGR programs, supplemented with BR or 6-BA and nutrients, can partially improve floral induction in ‘Ziniangxi’ under warm, low-chill winters and provide a basis for designing PGR strategies for late litchi cultivars facing insufficient winter chilling. Full article

The basic helix-loop-helix (bHLH) transcription factor ‘Atoh8’ is involved in the regulation of several developmental processes and pathologies. It regulates organogenesis, reprogramming, stem cell fate determination, and cancer development. However, the mechanisms underlying these observations remain unclear. Unlike many tissue-specific bHLH factors, Atoh8 is ubiquitously expressed during development as well as in adult tissues. In this study, we explored whether Atoh8 modulates basic cellular functions, which may reveal a common mechanism that could explain the diverse observations reported in the literature. Our findings demonstrate that the loss of Atoh8 impairs autophagy. In both primary myoblasts and mouse embryonic stem cells lacking Atoh8, we observed differential expression of LC3B-II, TFEB, and accumulation of p62, indicating impairment of autophagy. Furthermore, mass spectrometric analysis performed on C2C12 and Atoh8 overexpressing C2C12 myoblasts revealed significant alterations in the expression of proteins associated with mitochondrial and lysosomal functions. Finally, Cut&Tag sequencing performed in Atoh8 overexpressing C2C12 cells revealed that Atoh8 binds to multiple genes involved in autophagosome assembly. Overall, this study underscores that Atoh8 is a critical regulator of macroautophagy, and its reduction disrupts the autophagic process, whereas its overexpression results in increased autophagic flux. Full article

Lbx1 plays important roles in different processes, including the development of sensory pathways, neuronal cell fate regulation, and muscle cell precursor migration. Genetic variation in the LBX1 locus has been associated with several human disease conditions, such as idiopathic scoliosis, congenital limb malformation, and neuropsychiatric illness, including attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders. Zebrafish (Danio rerio) were used to investigate the behavioral consequences of the loss of function of the two orthologs to the human LBX1 gene, zebrafish lbx1a and lbx1b. We observed a consistent locomotor hyperactivity phenotype induced by a novel environment in lbx1a mutants. Repeated dark stimuli provoked similar responses in both mutant lines, including the novelty-induced hyperactivity. We performed RNAseq on total RNA isolated from the head region of mutant and wildtype larvae. Several differentially expressed genes were identified, giving more insights into Lbx1 target genes and pathways, which could be relevant regarding the evaluation of zebrafish lbx1a or lbx1b as a human disease model. Furthermore, the analysis was complemented with a comparison to the expression profile of human LBX1 overexpression in cell culture, revealing a convergence on just two commonly regulated genes, namely alpha-Internexin (INA) and Fibrillin-3 (FBN3). In conclusion, our findings might further elucidate the multitude of functions of Lbx1 and its involvement in various human disease conditions. Full article

Background/Objectives: The Notch signaling pathway regulates cell fate, proliferation, and differentiation, and its dysregulation has been implicated in various cancers, including breast cancer. MicroRNAs (miRNAs) are critical post-transcriptional regulators that can modulate Notch pathway components. The aim of this study was to identify miRNAs that may potentially regulate the expression of Notch pathway-related genes across five molecular subtypes of breast cancer in Polish women. Methods: Tumor and adjacent normal tissue samples were collected from 405 patients with five breast cancer subtypes: luminal A (n = 130), HER2-negative luminal B (n = 100), HER2-positive luminal B (n = 96), non-luminal HER2-positive (n = 36), and triple-negative breast cancer (n = 43). Gene expression was profiled using mRNA microarrays and validated with RT-qPCR and ELISA. Candidate regulatory miRNAs were identified by miRNA microarrays and confirmed using the miRDB database. Results: APH1A, CTBP1, DTX1, HEY1, HEY2, JAG2, NOTCH4, TLE2, and TLE4 were consistently dysregulated across all breast cancer subtypes. Overexpression of HEY1 and JAG2 may be driven by decreased levels of miR-145, miR-98, and miR-381. Conversely, downregulation of TLE4 may be associated with elevated expression of miR-196a and miR-155. No regulatory miRNAs meeting the selection criteria were identified for APH1A, CTBP1, DTX1, HEY2, NOTCH4, or TLE2. Conclusions: The consistent alterations suggest the presence of a shared Notch-driven oncogenic signature in breast cancer, potentially driving cell proliferation, stemness, and resistance to therapy. These findings enhance our understanding of Notch signaling in breast cancer and propose novel miRNA–Notch interactions as candidate targets for therapeutic intervention. Full article

Recent studies indicate that opportunistic gut bacteria contribute to the recurrence and chemoresistance in colorectal cancer (CRC); however, their fate after surgical resection remains poorly understood. This study investigated the longitudinal changes in these bacteria and assessed their potential persistence following CRC surgery. Forty fecal samples were collected from ten CRC patients at four timepoints: (1) pre-surgery (S); (2) one week (S1); (3) one month (S2); and (4) three months (S3) post-surgery. Fifteen other fecal samples were collected from healthy individuals as our study controls. Microbial profiling was performed using 16S rRNA gene sequencing, and quantitative PCR was applied to assess the changes in three opportunistic bacteria associated with CRC-associated. Our study revealed that Escherichia coli was significantly enriched in pre-surgical samples (S), while Enterococcus faecalis was predominant in the samples collected one-week after surgery (S1). All the assessed species showed a gradual post-surgical decline in relative abundance, suggesting they do not persist after resection. Additionally, there was a significant increase in relative abundance of beneficial bacterial signatures, including Akkermansia muciniphila, Bacteroides uniformis, Parabacteroides merdae, and Phascolarctobacterium faecium post-surgery, which implies a potential dysbiosis restoration. Our findings suggest that surgical resection gradually reduces the burden of opportunistic gut microbiota, thus gradually lowering the risk of recurrence and chemoresistance. Additionally, it may facilitate the restoration of beneficial taxa. Future studies should include extended follow-up periods to validate our findings and their correlation with clinical outcomes. Full article

RACK1 (Receptor for Activated C Kinase 1) is a highly conserved scaffold protein that functions as a central integrator within diverse cellular signaling pathways. Initially identified as a receptor for activated Protein Kinase C, it is now recognized as a dynamic platform coordinating processes such as cell proliferation, migration, apoptosis, and immune responses. A defining feature of RACK1 is its ability to direct cellular fate by determining whether proteins are synthesized or degraded. However, a unified model explaining this functional pleiotropy has been lacking. In this review, we synthesize current knowledge to propose an integrative model centered on a functional dimorphism driven by RACK1’s localization and post-translational modifications. We posit that RACK1 operates in two primary, mutually exclusive states: a ribosome-associated monomer that supports the translation of specific mRNAs and quality control, and a free monomer or dimer that governs signaling cascades and gene expression. Phosphorylation at key sites, such as Thr50 and Ser146, acts as a molecular switch, spatiotemporally redistributing RACK1 between these pools. This mechanism allows the cell to rapidly reprogram its proteomic landscape in response to stimuli, pivoting between protein synthesis and stress adaptation. Our model resolves the apparent dichotomy of RACK1’s roles by framing it as a cellular “resource manager,” whose regulated switching between functional states ensures an optimal response to the extracellular environment, with significant implications for understanding cancer and neurodegenerative diseases. Full article

The LATERAL ORGAN BOUNDARIES DOMAIN (LBD) gene family encodes plant-specific transcription factors that play vital roles in plant growth, development, and stress responses. Rice (Oryza sativa L.), a staple food for more than half of the world’s population, also serves as an important model organism for monocot functional genomics. In this study, we conducted a comprehensive genomic survey of the OsLBD gene family in Oryza sativa ssp. japonica using the latest genomic sequence data. A total of 35 members of this family were identified through systematic characterization of their gene structures, conserved domains, phylogenetic relationships, and chromosomal distributions. Our analysis indicated that the expansion of OsLBD genes may have resulted mainly from segmental duplication, with these duplicated genes exhibiting diverse evolutionary fates ranging from functional conservation to expression divergence. Phylogenetic analysis further classified the OsLBD genes into two major groups: Class I and Class II. Expression profiling across various developmental stages demonstrated dynamic spatiotemporal regulation, with certain genes exhibiting tissue-specific expression, particularly in reproductive tissues. Furthermore, a comprehensive co-expression analysis of OsLBD genes and their co-regulators revealed multiple modules with tissue-specific roles in pollen cell wall synthesis and endosperm glycogen biosynthesis. Promoter analysis identified several cis-regulatory elements associated with hormone responses, stress adaptation, and developmental processes, consistent with the observed expression patterns under phytohormone treatments. Comparative genomics revealed a higher degree of synteny between rice and barley than between rice and Arabidopsis, highlighting the evolutionary conservation within the Poaceae family. This study provides a foundational framework for understanding the biological functions of OsLBD genes in rice and identifies promising candidate genes involved in vegetative and reproductive growth, development, and stress responses. Full article