Search Results (883)

Recent evidence indicates that both epithelial-to-mesenchymal transition (EMT) and its reverse process, mesenchymal-to-epithelial transition (MET), are key mechanisms driving breast cancer (BC) metastasis. During EMT, epithelial BC cells acquire mesenchymal traits that enhance motility, invasiveness, and resistance to therapy. A deeper understanding of EMT regulation may therefore unveil novel therapeutic targets to limit disease progression. In this study, we analyzed the expression of key EMT-associated proteins, namely Vimentin, E-cadherin, Cytokeratin-18, and alpha-smooth muscle actin, in a cohort of 95 BC tissue samples and observed marked intra- and inter-tumoral heterogeneity. Notably, we found positive correlations between epithelial and mesenchymal markers, supporting the presence of hybrid epithelial/mesenchymal phenotypes and substantial cellular plasticity, which may contribute to BC heterogeneity. High heterogeneity in marker expression was also detected between tumor tissues and matched adjacent normal tissues. The unexpected complexity uncovered at the protein level prompted us to question whether single markers or limited proteomic panels are sufficient to capture the EMT landscape in BC. Through integrative bioinformatics, we defined a novel EMT gene signature significantly associated with prognosis. Functional enrichment revealed pathways related to extracellular matrix organization, proteoglycans, and intercellular communication, emphasizing the dynamic bidirectional crosstalk between BC cells and the tumor microenvironment. Moreover, we identified a gene cluster linked to cancer stem cell-like features, which may be clinically relevant for patient risk stratification. Overall, our findings underscore the complexity of EMT regulation in BC and introduce a new EMT signature with potential prognostic and therapeutic relevance. Full article

Palmitoylethanolamide (PEA) among N-acylethanolamides displays a noteworthy impact on different inflammatory conditions and promises to become a valuable anti-inflammatory tool that does not interfere with the cyclooxygenase pathway. Mounting evidence confirms the multi-dimensional PEA-mediated crosstalk between microglia and mast cells, which would open new therapeutic opportunities targeting a neuroimmune axis and influencing both health and disease. In particular, PEA acts as a preserver of cellular homeostasis by regulating microglia cell activity and inhibiting mast cell activation in the central nervous system. The improved bioavailability and efficacy of ultramicronized formulations of PEA reflect its ultimate usefulness for different clinical applications, including significantly relieving inflammation but also reducing the pro-inflammatory burden of complex patients with either neuropathies or non-neurologic afflictions. This review aims to comprehensively delineate the therapeutic potential of PEA beyond its mere indication for acute inflammation and to highlight PEA activity as a broad-spectrum pan-tissue protective agent through the results of different preclinical and also some clinical studies. Much more remains to be learned about further PEA mechanisms of action that regulate neuroinflammation, and additional studies will have to investigate the exact role of microglia and mast cells in inflammatory diseases. Full article

Adipocyte browning refers to the inducible transdifferentiation or de novo recruitment of thermogenically active beige adipocytes within white adipose tissue depots. Beige adipocytes, characterized by multilocular lipid droplets and high mitochondrial density, express uncoupling protein 1 and possess a metabolic phenotype similar to that of classical brown adipocytes. This plasticity of adipose tissue is regulated by a complex network of transcriptional coactivators (e.g., PRDM16, PGC-1α), epigenetic modulators, non-coding RNAs, and hormonal signals. Environmental cues, such as chronic cold exposure, exercise, and caloric restriction, further potentiate browning via sympathetic nervous system activation and endocrine crosstalk. At the systemic level, adipocyte browning enhances energy expenditure, improves insulin sensitivity, and mitigates lipid accumulation, making it a promising target for the treatment of obesity, type 2 diabetes mellitus, and other metabolic syndromes. Several browning agents (natural products and repositioned drugs) and novel chemicals that induce browning have been reported. However, the translational application of these agents in humans faces challenges related to interspecies differences, depot-specific responses, and long-term safety. This review critically examines molecular regulators, existing browning agents, and the discovery of novel browning agents, with the aim of harnessing them for metabolic disease intervention. Full article

This review proposes mechanical crosstalk between stromal tension and vascular shear/flow as a unifying principle for integrating fibroblast-populated collagen lattices (FPCLs) with perfusable micro-physiological systems (MPSs). We argue that current in vitro platforms either emphasize fibroblast-driven matrix contraction (as with FPCLs) or flow-mediated vascular dynamics (as with MPSs) but rarely consider the reciprocity between these forces. By defining a mechanobiological framework that couples cellular contractility, extracellular matrix (ECM) remodeling, and shear-dependent endothelial responses, we reframe FPCL–MPS hybrids as “living devices” capable of capturing mechano-transduction across stromal and vascular compartments. This review (1) delineates the mechanobiology of FPCLs, highlighting their tension generation, matrix remodeling, and disease relevance; (2) surveys perfusable MPS design principles, focusing on shear stress, barrier function, and multicellular integration; (3) formulates a crosstalk paradigm in which stromal tension and vascular shear coregulate tissue physiology; (4) synthesizes engineering strategies for integrating FPCLs into MPSs; and (5) outlines challenges and future directions involving multiscale measurements, multi-omics, artificial intelligence, and regulatory standardization. To our knowledge, this review is among the first to explicitly frame stromal tension and vascular shear as a unified mechanobiological axis. Full article

Tunneling nanotubes (TNTs) are dynamic cell surface conduits that enable direct transfer of ions, signaling molecules, and organelles. They have emerged as a key mechanism of intercellular communication, complementing classical pathways such as synapses and paracrine signaling. In the central nervous system (CNS), TNTs exhibit a functional duality, particularly under aging and stress, where TNT-mediated exchange may shift from protective to maladaptive. On one hand, TNTs support homeostatic functions, ranging from mitochondrial transfer to stem cell-mediated rescue and astrocyte–neuron metabolic support. On the other hand, they facilitate the spread of prions and neurodegenerative protein aggregates, such as Tau and α-synuclein, with astrocytes playing a regulatory role. Despite rapid advances, TNT research faces challenges from conceptual heterogeneity and experimental standardization, especially in complex tissues such as the CNS. Recent mechanobiological and bio-inspired approaches, including force-based assays and three-dimensional culture models, provide new insights into TNT formation, stability, and cargo transport, extending beyond neural systems. This review offers an integrative synthesis of molecular, structural, and mechanobiological principles underlying TNT-mediated communication, emphasizing astrocyte–neuron crosstalk, while proposing validation criteria to support rigor, reproducibility, and cross-study comparability. TNTs thus emerge as dynamic, context-dependent interfaces with broad relevance to neurodegeneration, cancer, and biomedical applications. Full article

Background: Adipose tissue surrounds organs and tissues in the body and can alter their function. It could secrete diverse biological molecules, including lipids, cytokines, hormones, and metabolites. In light of all this information, obesity can influence many tissues and organs in the body, and this situation makes obesity a central contributor to multiple disorders. It is very important to investigate the crosstalk between tissues and organs in the body to clarify the key mechanisms of obesity. Methods: In this study, we analyzed the gene expression profiles of the liver, skeletal muscle, blood, visceral, and subcutaneous adipose tissue. Differentially expressed genes (DEGs) were identified for each tissue, and functional enrichment and protein–protein interaction network analyses were performed on genes commonly identified across tissues. Priority candidate genes were identified using network-based centrality measures, and potential molecular intersection points were explored through host-pathogen interaction network analysis. This study provides an integrative framework for characterizing inter-tissue molecular patterns associated with obesity at the network level. Results: The muscle, subcutaneous adipose tissue, and blood have the highest number of DEGs. The subcutaneous adipose tissue and blood stand out due to the number of DEGs they possess, although liver and visceral adipose tissue have lower amounts. Cancer ranks first in terms of diseases associated with obesity, and this association is accompanied by leukemia, lymphoma, and gastric cancer. RPL15 and RBM39 are the top genes in both degree and betweenness metrics. The host–pathogen interaction network consists of 13 unique-host proteins, 54 unique-pathogen proteins, and 27 unique-pathogen organisms, and the Influenza A virus had the highest interaction. There were a small number of common metabolites in all tissues: 2-Oxoglutarate, Adenosine, Succinate, and D-mannose. Conclusions: In this study, we aimed to identify candidate molecules for obesity using an integrative approach, examining the gene profiles of different organs and tissues. The findings of this study suggest a possible link between obesity and immune-related biological processes. The network obtained from the host-pathogen interaction analysis, and especially the pathways associated with viral infections that stand out in the functional enrichment analysis, may overlap with molecular signatures linked to obesity. Furthermore, the co-occurrence of cytokine signaling, insulin, and glucose metabolism pathways in the enrichment results indicates that the response of cells to insulin may be affected in obese individuals, suggesting a potential interaction between immune and metabolic processes; however, further experimental validation is needed to reveal the direct functional effects of these relationships. Full article

Zinc homeostasis is fundamental to metabolic health, orchestrated by the coordinated actions of two major zinc transporter families: ZIP (Zrt- and Irt-like proteins) and ZnT (zinc transporters). ZIP transporters facilitate zinc influx into the cytosol from the extracellular space or from the lumen of intracellular organelles, whereas ZnT transporters control zinc efflux from the cytosol to the extracellular space or facilitate its sequestration into intracellular vesicles and organelles, concurrently harboring the meticulous intracellular zinc homeostasis. This equilibrium is essential for all critical functions like cellular response, metabolic control, and immune pathway alteration. Disruption of this homeostasis is a driver of different pathological alterations like metabolic inflammation, a chronic low-grade inflammatory state underlying obesity; type 2 diabetes; and nonalcoholic fatty liver disease. Recent studies revealed that ZIP and ZnT transporters dynamically regulate metabolic and inflammatory cues, with their tissue-specific expression varying by tissue and acclimating to different physiological and pathological conditions. Recent advanced research in molecular and genetic understanding has helped to deepen our knowledge of the interplay of activity between ZIP and ZnT transporters and their crosstalk in metabolic tissues, underscoring the potential therapeutic prospect for restoring zinc balance and ameliorating metabolic inflammation. This review provides a comprehensive overview that covers the function, regulation, and interactive crosstalk of ZIP and ZnT zinc transporters in metabolic tissues and their pathological conditions. Full article

Sarcopenic obesity, characterized by skeletal muscle loss concurrent with adipose tissue accumulation, has emerged as a global health threat. Exercise is established as an effective intervention; however, the molecular mechanisms underlying its protective effects remain incompletely defined. This study investigated whether exercise mitigates high-fat diet (HFD)-induced sarcopenic obesity, and whether the mechanism was related to the activation of the adenosine monophosphate-activated protein kinase (AMPK)/Acetyl-CoA carboxylase pathway (ACC) pathway and the inhibition of ferroptosis. Cell experiments demonstrated that palmitic acid induced ferroptosis in C2C12 mouse myoblasts. Animal experiments confirmed that HFD promoted skeletal muscle ferroptosis in C57BL/6 mice, evidenced by iron metabolism imbalance (solute carrier family 39 member14 upregulation, ferroportin downregulation), impaired antioxidant capacity (reduced glutathione, superoxide dismutase, glutathione peroxidase 4), and elevated lipid peroxidation (increased malondialdehyde). Meanwhile, both flat treadmill running and uphill treadmill running may reverse these changes by activating AMPK/ACC phosphorylation, reducing non-transferrin iron uptake, enhancing iron export and storage, and improving antioxidant status, jointly inhibiting ferroptosis and attenuating muscle mass loss and lipid deposition. These findings confirm that ferroptosis acts as one of the key pathogenic drivers in sarcopenic obesity and suggests that exercise may improve sarcopenic obesity by activating the AMPK/ACC pathway and inhibiting ferroptosis. This study provides novel mechanistic insights into exercise-mediated regulation of iron-lipid metabolism crosstalk and informs targeted interventions for sarcopenic obesity. Full article

Asparagine synthetase (AS) is a key enzyme in plant nitrogen metabolic network. Beyond its canonical role as a major nitrogen transport and storage molecule, asparagine also serves critical functions in plant immunity and tolerance to environmental stresses. This review systematically summarizes the characteristics of the core AS-mediated asparagine biosynthesis pathway and two other minor pathways in plants. It details the distribution of the AS gene family, protein structure, and evolutionary classification. The mechanisms governing AS expression are analyzed, revealing tissue-specific patterns and precise regulation by nitrogen availability, abiotic stresses, and exogenous hormones, mediated through an interactive network of cis-acting elements and transcription factors. Furthermore, the biological functions of AS are multifaceted: it influences plant biomass and nitrogen use efficiency by regulating nitrogen uptake, transport, and recycling during growth and development; it contributes to abiotic stress tolerance by synthesizing asparagine to maintain cellular osmotic balance and scavenge reactive oxygen species; and it indirectly enhances antibacterial and antiviral capacity by activating the SA signaling pathway and modulating programmed cell death. Current knowledge gaps remain regarding the crosstalk between AS-mediated signaling pathways, the upstream transcriptional regulatory network, and the balance between nitrogen utilization and disease resistance in crop breeding. Future research aimed at addressing these questions will provide a theoretical foundation and molecular targets for improving crop nitrogen use efficiency and breeding resistant cultivars. Full article

Hypoxia is a common feature of inflamed and ischemic tissues and represents an important regulatory signal for innate immune cells. The master regulator of this response is hypoxia-inducible factor-1α (HIF-1α), a transcription factor whose stabilization and activity are tightly regulated by the presence of oxygen, inflammatory signaling, and cellular metabolism. Monocytes, key players in innate immunity, rapidly sense oxygen deprivation and display specific responses during acute hypoxia, primarily aimed at adapting and maintaining cellular homeostasis. Unlike macrophages, in which HIF-1α activity is known, the mechanisms regulating HIF-1α stabilization, subcellular localization, and transcriptional activity in circulating monocytes remain incompletely elucidated. Recent studies indicate that acute hypoxia primarily triggers post-translational stabilization of HIF-1α, calcium- and PKC-dependent signaling, metabolic reprogramming, and early inflammatory responses, while transcriptional activation of HIF-1α may require additional inflammatory or stress-related signals. Furthermore, extensive crosstalk between HIF-1α and NF-κB integrates hypoxic and inflammatory signals, modulating cytokine production, cell migration, and survival. Epigenetic regulators can also modulate these responses and contribute to hypoxia-induced trained immunity. In this review, we summarize current knowledge of the mechanisms controlling the stabilization, localization, and function of HIF-1α in human monocytes and monocyte–macrophages during acute hypoxia, highlighting the key differences between these cell types and discussing their implications for inflammation, tissue homeostasis, and disease. Full article

Melatonin (MEL), also known as N-acetyl-5-methoxytryptamine, has been reported in plants as a secondary messenger involved in regulating abiotic stress responses. MEL treatment, either preharvest or postharvest, regulates several physiological and biochemical processes during fruit growth and ripening in horticultural products. These include reproductive development, tissue and quality maintenance, delayed senescence, and responses to abiotic stress. Due to its natural origin, low toxicity, and multifunctional regulatory capacity, MEL has recently attracted attention as a promising ‘green preservative’ for sustainable postharvest management. Additionally, MEL coordinates through cross-talk with other plant hormones, such as abscisic acid, ethylene, polyamines, jasmonic acid, γ-aminobutyric acid, salicylic acid, and nitric oxide, to regulate postharvest ripening and senescence. Furthermore, MEL enhances antioxidant systems and improves membrane integrity, thereby alleviating chilling injury and enhancing fruit firmness and colour. Notably, recent evidence highlights the innovative regulatory mechanisms of MEL involving redox homeostasis, hormone signalling reprogramming, and transcriptional modulation of stress-responsive pathways. MEL could therefore be considered an emerging, eco-friendly tool for prolonging the shelf-life of fruit and vegetables and maintaining their quality. This review summarises the mechanisms by which MEL contributes to plant stress resistance by regulating the biosynthesis and metabolism of stress tolerance and improving fruit quality. Full article

Colorectal cancer (CRC) progression and therapy resistance are driven in part by metabolic reprogramming and the persistence of cancer stem-like cells (CSCs). The seven in absentia homolog 2 (SIAH2)/with-no-lysine kinase 1 (WNK1) signaling axis has emerged as a potential regulator of these processes, yet its functional role in CRC metabolism and tumor–stroma crosstalk remains incompletely understood. Integrated analyses of The Cancer Genome Atlas–Colon Adenocarcinoma (TCGA-COAD) and Gene Expression Omnibus (GEO, GSE17538) datasets revealed significant upregulation of SIAH2 and WNK1 in CRC tissues, with strong positive correlations to glycolysis- and hypoxia-associated genes, including PFKP, LDHA, BPGM, ADH1A, ADH1B, and HIF-1α. Single-cell and clinical profiling further demonstrated preferential enrichment of SIAH2 in undifferentiated, stem-like tumor cell populations. Functional studies across multiple CRC cell lines showed that SIAH2 silencing suppressed proliferation, clonogenic growth, tumor sphere formation, and cell-cycle progression, whereas SIAH2 overexpression exerted opposite effects. Seahorse extracellular flux analyses established that SIAH2 promotes glycolytic capacity and metabolic flexibility. At the protein level, SIAH2 regulated glycolytic enzymes and WNK1/hypoxia-inducible factor-1α (HIF-1α) signaling, effects that were amplified by cancer-associated fibroblast (CAF)-derived conditioned medium. CAF exposure enhanced SIAH2 expression, CSC spheroid growth, and resistance to fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy, whereas SIAH2 depletion effectively abrogated these effects. Collectively, these findings identify the SIAH2/WNK1 axis as a central metabolic regulator linking glycolysis, CSC maintenance, and microenvironment-driven therapy resistance in CRC, highlighting its potential as a therapeutic target. Full article

Hydroxyprogesterone (HP) is a synthetic progestogen widely used in obstetric care, and its potential influence on breast cancer biology has become an emerging area of interest. Despite its clinical use, the molecular mechanisms by which HP affects tumor tissue remain insufficiently explored. In this study, transcriptomic profiling was performed to investigate gene expression changes associated with HP in operable breast cancer. Pre-operative 17α-HP caproate (17-OHPC) exposure was associated, in normal adjacent tissue (NAT), with activation of steroid-hormone and lipid/xenobiotic-metabolism programs and crosstalk to phosphoinositide 3-kinase (PI3K)–Akt and nuclear factor kappa B (NF-κB). In NAT, these pathways showed the largest absolute log₂ fold-change (|log₂FC|); significance is reported as false discovery rate (FDR) throughout (e.g., FKBP5↑ with HP). In tumor tissue, the dominant signal reflected tight-junction/apical-junction and extracellular matrix (ECM)-receptor remodeling (e.g., CLDN4↑). We prioritized FKBP5 (HP pharmacodynamics) and CLDN4 (tumor baseline) as the main candidates; TSPO and SGK1 are reported as exploratory. This discovery-level, hypothesis-generating analysis nominates candidate biomarkers and pathway signals for prioritization and evaluation in independent datasets and future studies. These findings provide mechanistic insight into HP’s molecular effects in breast cancer and suggest potential applications in biomarker perioperative management. Full article

Endometriosis is traditionally conceptualized as a pelvic lesion–centered disease; however, mounting evidence indicates it is a chronic, systemic, and multifactorial inflammatory disorder. This review examines the molecular dialog between ectopic endometrial tissue, the immune system, and peripheral organs, highlighting mechanisms that underlie disease chronicity, symptom variability, and therapeutic resistance. Ectopic endometrium exhibits distinct transcriptomic and epigenetic signatures, disrupted hormonal signaling, and a pro-inflammatory microenvironment characterized by inflammatory mediators, prostaglandins, and matrix metalloproteinases. Immune-endometrial crosstalk fosters immune evasion through altered cytokine profiles, extracellular vesicles, immune checkpoint molecules, and immunomodulatory microRNAs, enabling lesion persistence. Beyond the pelvis, systemic low-grade inflammation, circulating cytokines, and microRNAs reflect a molecular spillover that contributes to chronic pain, fatigue, hypothalamic–pituitary–adrenal axis dysregulation, and emerging gut–endometrium interactions. Furthermore, circulating biomarkers—including microRNAs, lncRNAs, extracellular vesicles, and proteomic signatures—offer potential for early diagnosis, patient stratification, and monitoring of therapeutic responses. Conventional hormonal therapies demonstrate limited efficacy, whereas novel molecular targets and delivery systems, including angiogenesis inhibitors, immune modulators, epigenetic regulators, and nanotherapeutics, show promise for precision intervention. A systems medicine framework, integrating multi-omics analyses and network-based approaches, supports reconceptualizing endometriosis as a systemic inflammatory condition with gynecologic manifestations. This perspective emphasizes the need for interdisciplinary collaboration to advance diagnostics, therapeutics, and individualized patient care, ultimately moving beyond a lesion-centered paradigm toward a molecularly informed, holistic understanding of endometriosis. Full article

Ferroptosis is a distinct form of regulated necrotic cell death driven by iron-dependent phospholipid peroxidation, characterized by flexible and context-dependent mechanisms rather than a single fixed linear pathway. This study elucidates the critical lipid peroxidation networks and antioxidant defense systems used in determining ferroptosis, specifically emphasizing how these mechanisms underpin the plasticity of this cell death mode and its correlation with therapeutic resistance. We examine the catastrophic propagation of ferroptosis, detailing the multi-layered amplification mechanisms—ranging from intracellular organelle crosstalk to intercellular trigger waves—that may facilitate massive tissue damage in degenerative diseases and ischemic injuries. Furthermore, the evolutionary conservation of ferroptosis-like phenomena across diverse species is summarized, underscoring its fundamental role in development and host–pathogen interactions. To conclude, we explore pivotal knowledge gaps that remain in our understanding of ferroptosis. By integrating these complex regulatory networks, this review provides a comprehensive framework for understanding ferroptosis as an adaptable, self-amplifying process, informing future efforts to modulate ferroptosis in disease contexts. Notably, this review focuses on the amplification, execution, and propagation phases of ferroptosis rather than on its initial triggering mechanisms, which remain an area of active investigation. Full article