Search Results (666)

The survival of complex multicellular organisms depends on continuous inter-organ communication networks that coordinate organism-wide responses across physiological conditions and stress states, including adaptation to environmental challenges, infection, and injury. Rather than operating as isolated units, organ systems are integrated through interconnected signaling networks that transmit biological information across tissues. Building on prior work examining individual physiological pathways, this review introduces a unified systems-level framework that integrates inter-organ communication into a coherent model of organism-wide regulation. This review proposes a systems-level framework in which homeostasis is maintained through eight principal communication systems: neural, endocrine, immune-inflammatory, vascular, lymphatic, metabolic, microbiome–gut, and mechanical-structural. Epithelial barriers function as dynamic signaling interfaces within multiple systems, while extracellular vesicles act as cross-system mediators of information transfer rather than as independent communication networks. These systems operate across distinct temporal scales to coordinate host defense, metabolic adaptation, vascular regulation, and tissue repair. The framework further introduces a temporal hierarchy of signaling dynamics that links communication systems to phase-specific responses during physiological stress. Within this integrated network, glucocorticoid receptor α (GRα) is proposed to function as a systems-level regulator of inter-organ communication, supported by converging mechanistic, experimental, and clinical evidence, with variability in the strength of evidence across domains. In contrast to prior reviews, which addressed GRα function within individual systems, this work conceptualizes GRα as a central rheostat coordinating cross-system signaling and temporal transitions in homeostatic correction. Evidence was identified through hypothesis-driven searches using the Consensus AI platform and verified through manual review of primary biomedical literature. GRα, a ligand-activated transcription factor expressed in most nucleated cells, enables hormonal stress signals to coordinate gene-expression programs across tissues, modulating neuroendocrine responses, endothelial function, inflammatory signaling, metabolic regulation, microbiome–host interactions, and tissue remodeling. Systemic responses to stress progress through three phases of homeostatic correction—Priming, Modulatory, and Restorative—within which GRα supports integrated organism-wide adaptation. This integrative framework provides a mechanistic basis for understanding the emergence and temporal evolution of biological responses in health and critical illness. Full article

Osteoporosis and hyperglycemia are increasingly recognized as dual public health concerns in T1DM. However, the precise molecular mechanisms by which exercise ameliorates these conditions, particularly the contribution of mechanosensitive channels such as Piezo1, remain incompletely elucidated. To explore these mechanisms, T1DM mice were subjected to a 6-week treadmill training protocol (15 m/min, 20 min/day, 6 days/week) to evaluate the functions of exercise on diabetic osteoporosis and hyperglycemia. Exercise intervention markedly improved bone quality in T1DM mice, alleviating osteoporotic manifestations, as evidenced by enhanced mechanical strength, restored bone microarchitecture, and normalized histomorphology. Concurrently, exercise significantly reduced hyperglycemia. To clarify the role of Piezo1, mechanical stretch was applied to Piezo1-knockout MC3T3-E1 (Piezo1^−/−) cells in vitro, mimicking the mechanical stimulation induced by exercise. Consistent with the in vivo results, mechanical stimulation facilitated osteogenic differentiation and glucose metabolism through Piezo1-mediated mechanotransduction. Importantly, these beneficial effects were substantially abrogated in Piezo1^−/− cells, highlighting the central role of Piezo1. Collectively, these findings demonstrate that Piezo1-mediated mechanotransduction constitutes a critical factor by which exercise mitigates osteoporosis and hyperglycemia in T1DM mice. This study provides a framework for the development of new therapeutic strategies targeting Piezo1-mediated mechanotransduction for T1DM management. Full article

Heritable thoracic aortic diseases (HTAD) are inherited conditions that increase the risk of thoracic aortic aneurysms, dissections, and premature aortic rupture. Advances in human genetics and experimental models have transformed our understanding of these disorders from a phenotype-based classification system to a mechanism-based view involving extracellular matrix (ECM) architecture, transforming growth factor-β (TGFβ) signaling, and vascular smooth muscle cell contractility. Marfan syndrome, Loeys–Dietz syndrome, and nonsyndromic HTAD demonstrate how genetic mutations can disrupt the components that stabilize the aortic wall. These pathogenic mechanisms influence matrix organization, intracellular signaling, and the contractile machinery within the mechanically stressed proximal aorta. In this review, we summarize current mechanistic insights into the major forms of HTAD and discuss how new molecular and cellular concepts could influence surveillance, genetic counseling, and genotype-guided therapeutic strategies. Full article

Orthodontic tooth movement (OTM) is driven by force-induced alveolar bone remodeling, yet the molecular mechanisms by which periodontal ligament stem cells (PDLSCs) sense and transduce mechanical signals remain incompletely understood. Here, we identify the epigenetic regulator HELLS as a compressive force-responsive gene and investigate its role as a mechanosensitive mediator in human PDLSCs (hPDLSCs). Compressive force downregulated HELLS expression both in vitro and in a mouse OTM model. Functionally, siRNA-mediated HELLS knockdown impaired osteogenic differentiation, as evidenced by reduced Alizarin Red S staining and alkaline phosphatase activity, and induced global transcriptomic changes indicative of altered mechanotransduction pathways. Moreover, HELLS knockdown increased YAP and RANKL expression and potentiated osteoclast differentiation of co-cultured RAW264.7 cells. Finally, we identified E2F1 as a candidate transcription factor mediating the force-induced downregulation of HELLS. Collectively, these findings establish HELLS as a potential mechano-epigenetic regulator in hPDLSCs, and suggest that its force-induced downregulation may contribute to alveolar bone remodeling during OTM by simultaneously attenuating osteogenesis and enhancing pro-osteoclastogenic signaling via transcriptional reprogramming. Full article

Background: Atherosclerosis preferentially develops at arterial regions exposed to low shear stress (LSS), highlighting the critical role of local hemodynamic forces in disease initiation and progression. Emerging evidence indicates that endothelial lipid metabolism is a key determinant of vascular homeostasis; however, whether LSS directly regulates endothelial lipid droplets’ (LDs) dynamics remains unclear. In particular, the mechano-transduction pathways linking shear stress to lysosome-mediated lipid processing within the endothelium have yet to be defined. Methods: Complementary in vitro flow systems and in vivo atheroprone models were employed to examine the effects of LSS on endothelial lipid metabolism. Endothelial LDs accumulation, lysosome-dependent lipophagy, and atherosclerotic lesion development were systematically assessed under LSS conditions. Mechanistically, molecular profiling and rapamycin-mediated functional rescue were conducted to delineate the role of the KLF4/TFEB/ATP1A1 signaling axis in LSS-induced impairment of lysosome-dependent lipophagy. Results: We found that LSS induced pathological accumulation of LDs in vascular endothelial cells, accompanied by a marked suppression of lysosome-dependent lipophagy. Elucidation of the mechanism showed that LSS downregulated the shear-responsive transcription factor KLF4, resulting in aberrant phosphorylation of transcription factor EB (TFEB) and impaired TFEB nuclear translocation. Consequently, the TFEB transcriptional program governing lysosomal function was disrupted, including reduced expression of the TFEB target ATP1A1, leading to defective lysosomal acidification and blockade of lipid autophagic flux. Restoration of the KLF4/TFEB/ATP1A1 axis reactivated lipophagy, alleviated endothelial lipid burden, and significantly attenuated atherosclerotic lesion development. Conclusions: Our findings demonstrate that disruption of the KLF4/TFEB/ATP1A1 signaling pathway mediates LSS-induced impairment of endothelial lipophagy, thereby driving pathological LDs accumulation. This highlights the potential of restoring this axis as a therapeutic strategy to attenuate atherosclerotic progression. Full article

Background: Macrophages were long regarded as passive executors of erythrophagocytosis responsible for systemic iron recycling. However, increasing evidence has reframed them as immunometabolic hubs that sense diverse environmental cues to modulate systemic iron homeostasis. Main body: This review examines the molecular architecture underlying macrophage iron metabolism and outlines how iron metabolic processes are dynamically regulated across spatial and temporal scales through the integration of mechanotransductive, mitochondrial, and epigenetic signaling pathways. Across disease contexts, macrophage iron handling displays marked heterogeneity, exemplified by contact-dependent iron transfer in tumors and ferroptosis-driven instability in cardiovascular disease. In cardiovascular pathologies, iron overload is associated with enhanced ferroptosis-related cascades that contribute to atherosclerotic plaque instability. Furthermore, at mucosal interfaces, host–pathogen competition over nutritional immunity highlights epigenetic strategies by which pathogens perturb host iron machinery. Conclusions: Linking these mechanistic insights to clinical translation, emerging therapeutic strategies are discussed that move beyond non-specific systemic iron chelation toward more targeted interventions. These include engineering macrophages for targeted drug delivery, exploiting nanomedicine-based redox modulation to influence macrophage phenotypes, and non-invasive regulation via the gut microbiota–epigenetic axis. Collectively, elucidating macrophage iron metabolic networks provides a conceptual framework for the development of precision approaches to inflammatory, metabolic, and malignant diseases. Full article

The endothelial glycocalyx (EG) is a dynamic endothelial surface layer composed of proteoglycans, glycosaminoglycans, glycoproteins, and adsorbed plasma proteins that regulates permeability, mechanotransduction, leukocyte trafficking, coagulation, and nitric oxide signaling. In kidney transplantation (KT), the EG is exposed to cumulative injury from recipient uremia, donor instability, preservation, machine perfusion, reperfusion, rejection, and immunosuppressive toxicity. This narrative review summarizes EG biology in KT, with emphasis on biomolecular findings relevant to ischemia–reperfusion injury, delayed graft function, rejection, and chronic allograft injury. Particular attention is given to syndecan-1, heparan sulfate, heparanase, soluble thrombomodulin, matrix metalloproteinases, angiopoietin-2/Tie2 signaling, selectins, miR-126, extracellular vesicles, and urinary or perfusate-derived readouts. Current evidence is biologically coherent but uneven: human data are largely observational, whereas many therapeutic concepts remain preclinical or exploratory. Glycocalyx-centered phenotyping may eventually improve risk stratification and trial enrichment, but clinical implementation will require standardized sampling, sample-source-aware biomarker panels, prospective validation, and clear separation between mechanistic plausibility and proven clinical utility. Full article

Caveolin-1 (CAV1) is a 21 kDa Vesicular Integral-membrane Protein essential for the biogenesis of caveolae, invaginations of the plasma membrane that coordinate membrane trafficking, lipid homeostasis, and signal transduction. CAV1 functions as a scaffolding platform that integrates mechanotransduction, endocytosis, and cellular stress responses, thereby modulating vascular integrity, inflammation, metabolism, and tumorigenesis. To comprehensively understand the phosphorylation landscape of CAV1, global phosphoproteomic datasets and their corresponding experimental metadata were systematically curated and integrated from previously published human cellular studies. The phosphorylation sites with the highest detection frequency across these datasets were considered predominant phosphorylation sites. To assess their functional relevance, phosphosites in other proteins (PsOPs) co-regulated with the predominant CAV1 sites, along with their upstream kinases and high-confidence protein–protein interaction partners, were systematically analyzed. Analysis of global human cellular phosphoproteome datasets revealed that tyrosine 14 (Y14) and serine 37 (S37) of CAV1 are the most frequently detected phosphosites across diverse experimental conditions. Notably, many of the co-regulated proteins obtained were associated with carcinogenesis, apoptosis, and cell cycle regulation, including MET and ERBB2. Our analysis revealed SRC, ABL2, ERBB2, ERBB3, LYN, and TEC as potential upstream kinases of CAV1_Y14, whereas CSNK1E and GRK5 were predicted to regulate CAV1_S37. Considering the challenges associated with site-specific interrogation, we employed a global co-regulation analysis approach to characterize CAV1 phosphorylation dynamics. Our findings reveal that key CAV1 phosphosites modulate oncogenic signaling, cytoskeletal remodeling, and membrane organization, providing novel insights into CAV1-mediated cellular functions and its context-dependent role in tumor progression. Full article

Glioblastomas (GB) are highly aggressive brain tumors with poor patient prognosis and low survival rates. To identify novel therapeutic targets, the tumor microenvironment (TME) is increasingly examined, with a particular focus on biomechanical changes in the extracellular matrix (ECM) that contribute to GB aggressiveness. In GB, the ECM stiffens, regulating cell behavior through mechanotransduction. Preclinical in vitro and ex vivo studies generally report increased stiffness in GB relative to healthy brain tissue, whereas clinical in vivo measurements often report decreased stiffness. This review examines potential causes for this discrepancy, highlighting both biological and technical factors. Preclinical measurements are frequently performed using atomic force microscopy (AFM), while clinical stiffness is assessed via magnetic resonance elastography (MRE). Differences in methodology, including sample preparation, measurement modalities, and spatial scale, partly explain divergent stiffness values. Biological factors such as necrosis, edema, and physical confinement by the skull, which are preserved only in vivo, also contribute to these differences. To reconcile these findings, future research should employ physiologically relevant in vitro models that better replicate in vivo GB biomechanics, together with high-throughput and accurate animal models. Integrating these approaches may clarify the biomechanical landscape of GB and result in more effective therapeutic strategies. Full article

Big Bang theories are connected to gravity by force of attraction. Forced lengthening, like eccentric contractions, instigate proprioception as a result of working against gravity. Piezo2, as the principal mechanosensory ion channel responsible for proprioception, is theorized to fine-modulate these anti-gravitational contractions in order to provide system-wide ultrafast postural control. This mechanism may instantaneously emit energy and force through Piezo2 in order to offset gravity by anti-gravity entropic-spring-like stochastic mechanics and it is suggested to be propagated by quantum tunneling of protons (and electrons). However, a Piezo2-initiated wormhole-like mechanism with the contribution of cryptochromes should be considered as part of this ultrafast long-distance non-synaptic neurotransmission, although the quantum gravity concept is short of being unequivocally proven to be unified with quantum theory. The impairment of this theoretical ultrafast signaling is analogous to a Big Bang-like mechanism within a given compartment, or acquired Piezo2 channelopathy, leading to the principal gateway to pathophysiology. Full article

Exosomal microRNAs (miRNAs) are key mediators of intercellular communication in the breast cancer tumor microenvironment (TME), facilitating bidirectional signaling between malignant cells and the desmoplastic stroma. This review explores current evidence on their dual roles as drivers of stromal remodeling and as circulating biomarkers of therapeutic resistance across major breast cancer subtypes, including triple-negative breast cancer (TNBC), hormone receptor-positive (ER+/PR+) disease, and HER2-amplified tumors. We outline how miR-9, miR-21, and miR-181 family members promote cancer-associated fibroblast (CAF) activation, increase extracellular matrix (ECM) stiffness, and sustain a reverse Warburg phenotype. We then detail subtype-specific resistance mechanisms: miR-181 family members suppress BCLAF1 to block doxorubicin-induced apoptosis; miR-221/222 downregulates ESR1 and p27Kip1 to confer tamoxifen resistance; miR-155 impairs homologous recombination in TNBC; and miR-1246 sustains PI3K/AKT signaling in HER2-positive disease. We also evaluate circulating exosomal miRNA panels as liquid biopsy tools for predicting chemotherapy response and tracking resistance emergence. Finally, we discuss therapeutic strategies including antagomirs, miRNA replacement therapy and engineered exosome platforms, and address key challenges such as assay standardization and regulatory hurdles, that must be overcome for clinical translation. Full article

Nuclear lamins organize the structural and regulatory architecture of the nucleus, integrating nuclear mechanics, chromatin organization, and genome regulation. During cardiac development, lamin composition undergoes a coordinated transition that parallels the shift from proliferative embryonic cardiomyocytes to mechanically active postnatal cells. Recent findings reveal that B-type lamins support early nuclear plasticity and proliferative capacity, whereas Lamin A/C stabilizes nuclear architecture and transcriptional programs in mature cardiomyocytes. Beyond their structural roles, lamins participate in multiple layers of nuclear regulation, including lamina-associated chromatin organization, nucleo–cytoskeletal mechanotransduction, nucleocytoplasmic transport, and regulation of mitotic progression and cell-cycle exit. Through these interconnected functions, the nuclear lamina coordinates cardiomyocyte proliferation, maturation, and mechanical stress adaptation during heart development. Mutations in lamin genes cause a diverse group of disorders collectively known as laminopathies, many of which prominently affect the cardiovascular system. In this review, we first examine how B-type and A-type lamins are developmentally deployed to regulate cardiomyocyte proliferation and maturation in the heart. We then discuss the mechanistic pathways through which lamins organize nuclear architecture, chromatin dynamics, and nucleo–cytoskeletal signaling to coordinate cardiac cellular function. Finally, we consider how disruption of these lamin-dependent regulatory networks contributes to cardiomyopathy, cardiovascular aging, and the loss of regenerative capacity in the adult mammalian heart. Full article

We developed a multi-channel and multilayered polydimethylsiloxane (PDMS) microfluidic platform that integrates cyclic mechanical stimulation, independent reagent delivery, and real-time optical observation within a single device. The platform employs a four-layer architecture comprising a pneumatic valve control layer, an observation channel for cell culture and imaging (24 mm × 4 mm), a medium perfusion layer with independent inlet ports, and a vacuum actuation layer that deforms a 200 μm PDMS membrane under −20 kPa cyclic pressure at 1 Hz. Cyclic membrane strain of 10% was calibrated using fluorescent bead tracking and image analysis. Finite element analysis based on nonlinear Föppl–von Kármán plate theory confirmed that the central cell culture region (60% of membrane area) exhibits a mean von Mises strain of 14.2% with a uniformity of 81.3% (CV = 18.7%), validating relatively uniform mechanical stimulation across the culture surface. As a proof-of-concept, human aortic smooth muscle cells (CRL-1999) cultured under cyclic strain showed significant upregulation of HIF-1$\alpha$ expression (2.5-fold, $p<0.01$) and pronounced F-actin stress fiber alignment visualized by fluorescence microscopy, confirming the platform’s capability for mechanotransduction studies and real-time cellular observation. The multi-channel architecture enables multi-condition parallel testing by simultaneously introducing different reagent concentrations through independent inlet ports while maintaining identical mechanical parameters across all channels, providing a versatile tool for systematic investigation of cellular responses under controlled biomechanical conditions. Full article

This study evaluates how titanium and polymethyl methacrylate (PMMA) Boston Keratoprosthesis backplate substrates influence human corneal fibroblast proliferation, cytotoxicity, morphology, activation phenotype, and mechanotransductive signaling. Human corneal fibroblasts were cultured on titanium and PMMA, with tissue culture plastic or glass as controls. Proliferation was assessed over 7 days using metabolic assays, and cytotoxicity was measured by lactate dehydrogenase release. Cell morphology and surface coverage were examined by scanning electron microscopy, while immunofluorescence quantified fibroblast-specific protein 1 (FSP-1) and α-smooth muscle actin (α-SMA). Gene expression of α-SMA, collagen I, FSP-1, and focal adhesion kinase (FAK) was analyzed by quantitative PCR. Cells cultured on both substrates maintained stable viability with modest increases in estimated cell numbers and comparable proliferation curves, indicating preserved metabolic activity without growth suppression. Cytotoxicity remained low and similar between groups. SEM demonstrated broader and more continuous cell spreading on titanium, whereas cells on PMMA were more sparsely distributed. Immunofluorescence showed higher FSP-1 expression on titanium and increased α-SMA on PMMA. Gene expression analysis revealed higher FAK transcripts on PMMA, with no significant differences in α-SMA, FSP-1, or collagen I. These results confirm the cytocompatibility of both titanium and PMMA backplates with human corneal fibroblasts and support their use with the Boston Keratoprosthesis. Full article

Bone is a hierarchically organized composite material with unique mechanical properties and an intrinsic regenerative capacity that conventional repair strategies, including autografts, allografts, xenografts, and metallic or ceramic implants, fail to fully replicate due to donor scarcity, immunogenicity, mechanical mismatch, and poor long-term integration. Bone tissue engineering (TE) offers a biologically informed alternative by integrating osteoconductive scaffolds, osteogenic progenitor cells, and osteoinductive signaling molecules into a unified regenerative framework. Unlike existing reviews that evaluate these components in isolation, this review provides a mechanistically integrated analysis that repositions scaffold design as a biologically instructive platform whose topography, stiffness, porosity, and surface chemistry collectively govern cell adhesion, mechanotransduction, osteogenic differentiation, and extracellular matrix remodeling. Critically, it moves beyond cataloging materials and fabrication approaches to evaluate how specific scaffold features drive biological outcomes and to identify frequently understated limitations, including polymer-ceramic degradation kinetics and the inadequacy of small-animal models for clinical translation. By synthesizing advances in biomaterials, additive manufacturing, and smart scaffold technologies within this integrative framework, this review provides researchers and clinicians with a structured framework for evaluating emerging strategies and prioritizing future directions in functional bone regeneration. Full article