Search Results (424)

Metastatic colorectal cancer (mCRC) accounts for 90% of CRC-related mortality. This review synthesizes insights from comparative genomics tracing evolutionary trajectories from primary tumor to disseminated disease. Multi-region sequencing reveals metastatic seeding often occurs early—before clinical detection—challenging linear progression models. The metastatic bottleneck reduces clonal diversity while enriching for dissemination-competent traits including SMAD4 loss, PTEN inactivation and metabolic reprogramming. Organ-specific adaptation yields distinct molecular signatures: liver metastases exhibit Wnt hyperactivation and TGF-β-driven immune suppression; peritoneal tumors display mucinous features; brain metastases show HER2 enrichment. The immune microenvironment evolves toward immunosuppressive configurations, with Microsatellite instability high (MSI-H) tumors acquiring B2M or JAK1/2 mutations. Circulating tumor DNA (ctDNA) enables real-time tracking of clonal dynamics, detecting molecular residual disease months before radiographic progression. Therapeutic resistance follows predictable evolutionary trajectories—from RAS/BRAF mutations to EGFR ectodomain alterations, HER2/MET amplifications and lineage plasticity—with metastasis-specific mechanisms including microenvironmental protection and cellular dormancy. The clinical future lies in interception: leveraging liquid biopsies for early detection, targeting both tumor-intrinsic vulnerabilities and permissive metastatic niches and adapting therapy dynamically to anticipate resistance. Understanding this genomic odyssey is essential for transforming mCRC into a controllable chronic condition. Full article

Osteosarcoma (OS), the most common primary malignant bone tumor in children and young adults, is characterized by aggressive behavior, frequent metastasis, and resistance to chemotherapy, resulting in poor clinical outcomes. Increasing evidence indicates that OS progression is not solely driven by tumor-intrinsic factors but is strongly influenced by dynamic interactions within the tumor microenvironment (TME). This literature review synthesizes current research on the roles of endothelial cells, fibroblasts, mesenchymal stromal cells, immune populations, and osteoclasts in OS pathogenesis, with emphasis on cell–cell interactions mediated by direct contact, soluble factors, and extracellular vesicles. The studies demonstrate that these interactions promote tumor proliferation, immune evasion, extracellular matrix remodeling, metastatic dissemination, and therapeutic resistance. Adaptive responses of both tumor and stromal cells to environmental stressors contribute to chemoresistance and disease progression. Collectively, our findings highlight the multifactorial nature of OS driven by complex cellular crosstalk within the TME. Understanding these mechanisms highlights the limitations of conventional chemotherapy and encourages the development of combined therapeutic approaches, including targeted therapies, immunomodulation, and microenvironmental interventions. Continued investigation into tumor–microenvironment interactions may facilitate the identification of actionable targets and improve personalized treatment approaches for OS. Full article

The regeneration and repair of scarless skin tissue remain a significant challenge for full-thickness wounds. Traditional wound management approaches, particularly passive healing through scabbing and conventional mechanical debridement, are frequently associated with significant pain, high infection risks, and abnormal scar formation, often failing to support the regeneration of skin appendages like hair follicles. In recent years, collagen-based scaffolds have been widely adopted in tissue-engineered skin substitutes owing to their favorable biocompatibility. However, their simplistic, single-component architecture inherently lacks the dynamic, cell-instructive microenvironment found in native skin, which not only compromises the long-term survival and functional integration of seeded cells but also directly leads to insufficient reconstruction of the dermo-epidermal junction, thereby impairing skin barrier function and ultimately limiting overall regenerative efficacy. In this study, we propose a biomimetic multilayer composite scaffold system in which decellularized amniotic membrane matrix (AM) is combined with fibroblast-laden collagen gel (FCG) and seeded with epidermal stem cells (EpiSCs). This bionic skin (denoted as AM-FCG-EpiSCs) is designed to achieve hierarchical regeneration of full-thickness skin defects. Compared with injured skin treated with Moropicin ointment, the injured skin treated with AM-FCG-EpiSCs healed more quickly and regenerated appendages like hair follicles without scarring. The results show that the biomimetic structure of AM-FCG-EpiSCs can mediate dynamic cell–cell interactions and regulate the microenvironment. This breakthrough overcomes the dual challenges of scar suppression and functional restoration in full-thickness skin regeneration, offering an innovative solution for translational medicine. 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

Nephrolithiasis is a prevalent urological disorder worldwide, whose pathogenesis involves a complex network of crystal formation, cellular injury, and microenvironmental dysregulation. As a critical mechanism for regulating cellular functions, protein post-translational modifications (PTMs) have been increasingly implicated in multiple facets of kidney stone formation, including crystal–cell interactions, oxidative stress responses, and inflammatory signaling pathways. This review systematically synthesizes the biochemical foundations of PTMs, the molecular microenvironment of nephrolithiasis, and the roles of key modifications such as phosphorylation and acetylation in the pathogenesis of calculi. It further explores the translational potential of PTM detection technologies in clinical practice. Current evidence indicates that PTMs influence the nucleation, growth, and aggregation of crystals by modulating the activity of pro-/anti-lithogenic proteins, the expression of cell adhesion molecules, and inflammatory pathways. Consequently, therapeutic strategies targeting PTMs may offer novel avenues for the prevention and management of kidney stones. Future research should focus on integrating multi-omics approaches with functional validation to elucidate the dynamic regulatory networks of PTMs within the stone microenvironment, thereby advancing the development of precision medicine. Full article

Bone is a dynamic and multifunctional tissue that provides mechanical support, regulates mineral homeostasis, supports hematopoiesis, and relies on complex interactions among multiple cell types. The increasing incidence of bone-related diseases, such as osteoporosis, osteoarthritis, fracture non-union, and bone cancer, highlights the need for in vitro models that better reflect human bone physiology. Bone-on-a-chip technology, developed through advances in microfluidics, biomaterials, and tissue engineering, offers a promising approach to recreate key features of the bone microenvironment in vitro. By incorporating bone-mimicking materials, relevant bone cells, vascular components, fluid perfusion, and mechanical stimulation, these platforms allow more realistic investigation of bone remodeling, regeneration, disease mechanisms, and drug responses. In parallel, bone organoids and their integration with microfluidic chips have further expanded the capabilities of in vitro bone models by enabling the formation of self-organized, human-relevant bone tissues with increased cellular complexity. This review summarizes recent progress in bone-on-a-chip systems, including models for osteogenesis and bone regeneration, vascularized bone, bone marrow and hematopoietic niches, cancer bone metastasis, and mechanobiological studies. Key design principles, materials, cellular components, and applications in disease modeling, drug screening, toxicity assessment, and personalized medicine are discussed. Current challenges and future directions are also discussed to support the continued development of more physiologically relevant in vitro bone models. Full article

Background/Objectives: Alzheimer’s disease (AD) involves amyloid and tau pathology with neuroimmune dysregulation, and Yixin Yangshen Granules (YXYS) shows neuroprotective promise, though mechanisms remain unclear. This study aimed to elucidate the multi-target mechanisms of YXYS in AD. Methods: The study began by analyzing a public human AD hippocampal snRNA-seq dataset to identify cell-type-specific pathological pathways and profiled YXYS constituents by UPLC-QTOF-MS. In vitro, YXYS cytoprotection against mitochondrial dysfunction and oxidative stress was tested in Aβ_25–35-challenged HT22 cells; in vivo efficacy was assessed in Aβ_1–42-induced mice via behavioral and histopathological analyses. Integrated transcriptomic and proteomic profiling of brain tissue, with ELISA, qRT-PCR, and Western blot validation, confirmed pathway targets. Using the intersection of transcriptomic and proteomic targets as biological input, the DTIAM deep learning framework was employed to prioritize active YXYS constituents. Finally, molecular docking and 100-ns dynamics simulations demonstrated direct binding of Ganosporelactone A to HIF−1α. Results: AD snRNA-seq analysis highlighted HIF−1 and AGE-RAGE signaling as prominent pathways in the AD hippocampus, particularly enriched in brain microvascular endothelial cells, implicating neurovascular hypoxic and inflammatory stress. In Aβ-induced mice, YXYS improved cognition, reduced Aβ pathology, suppressed neuroinflammation, and promoted neuronal survival, consistent with in vitro evidence of restored mitochondrial function. Multi-omics confirmed convergence on HIF−1 and AGE-RAGE pathways, with YXYS rebalancing the neuroimmune microenvironment by reducing pro-inflammatory M0 macrophages. Screening against these consensus signaling hubs, deep learning analysis prioritized Ganosporelactone A as the top-ranked modulator, and molecular further demonstrated the stable binding of Ganosporelactone A to HIF−1α, linking YXYS to mitigation of hypoxic stress. Conclusions: Guided by multi-omics and deep learning, our findings suggest that YXYS may alleviate AD-related phenotypes through multi-target modulation of the HIF−1 and AGE-RAGE pathways, with associated improvements in neuro-immune homeostasis and reductions in oxidative stress, neuroinflammation, and hypoxia. Full article

Malignant transformation of benign salivary gland tumors represents a critical biological process that provides valuable insights into head and neck carcinogenesis, with potential implications for oral squamous cell carcinoma (OSCC). Understanding the molecular, epigenetic, and microenvironmental mechanisms underlying this transition is essential for improving early diagnosis, risk stratification, and personalized management strategies. This study presents a comprehensive narrative review of the current literature focusing on benign salivary gland tumors with malignant potential, particularly pleomorphic adenoma and carcinoma ex pleomorphic adenoma, emphasizing molecular alterations, angiogenesis, and tumor microenvironment dynamics. A structured literature search was conducted across major biomedical databases, including PubMed and Scopus, selecting studies that addressed genetic rearrangements, epigenetic modifications, histopathological features, and clinical connections of malignant transformation. The findings highlight recurrent genetic alterations such as PLAG1 and HMGA2 rearrangements, TP53 mutations, and ERBB2 overexpression, along with epigenetic dysregulation through CpG island hypermethylation. Enhanced angiogenesis, marked by increased expression of CD105 and vascular endothelial growth factor, as well as a “cold” immune microenvironment, emerged as key contributors to tumor progression. These mechanisms demonstrate significant overlap with pathways implicated in OSCC development. Benign salivary gland tumors represent a valuable model for studying malignant transformation in head and neck oncology. Interpreting shared molecular and microenvironmental pathways may facilitate the identification of novel biomarkers and support the development of personalized diagnostic and therapeutic approaches for OSCC. Full article

Background: Polysaccharide-based dynamic hydrogels are promising for wound management due to their biocompatibility, injectability, and tunable biofunctionality. The integration of therapeutic gasotransmitter donors offers a strategy to modulate the wound microenvironment. Objectives: This study aimed to develop an injectable, self-healing carbohydrate hydrogel capable of sustained hydrogen sulfide (H₂S) release for burn wound therapy, and to evaluate its physicochemical properties, in vivo efficacy, and mechanism of action. Methods: A dynamic hydrogel (ACMOD) was fabricated via Schiff-base crosslinking between oxidized dextran (OD) and carboxymethyl chitosan (CMCS), incorporating the H₂S donor 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH). Rheological and recovery tests characterized its mechanical and self-healing properties. Efficacy and mechanisms were assessed in a rat full-thickness burn model, analyzing wound closure, histology, oxidative stress, macrophage polarization, angiogenesis, and collagen deposition. Results: ACMOD exhibited shear-thinning, rapid self-healing, and strong tissue adherence. Sustained H₂S release from ACMOD significantly accelerated wound closure and improved tissue regeneration compared to controls. Mechanistically, H₂S attenuated oxidative stress, promoted a pro-regenerative M2 macrophage phenotype, enhanced angiogenesis via VEGF upregulation, and fostered organized collagen deposition and extracellular matrix remodeling. Conclusions: This work demonstrates a versatile, carbohydrate-based dynamic hydrogel platform that synergizes polymer network dynamics with bioactive H₂S delivery to effectively promote burn wound healing. The findings underscore the potential of polysaccharide hydrogels with integrated gasotransmitter release for regenerative therapy and biomaterials applications. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer death, characterized by poor prognosis in advanced stages despite available therapies. Dysfunctional mitochondrial can initiate both tumor progression and antitumor immunity. Altered mitochondrial quality control mechanisms, including dynamics, biogenesis, and degradation, contribute to mitochondrial decline supporting hepatocarcinogenesis and tumor survival. Within the immunosuppressive tumor microenvironment, HCC cells shift their metabolism toward glycolysis, which reduces nutrient availability and triggers mitochondrial dysfunction in infiltrating immune cells, leading to T-cell exhaustion and weakened cytotoxic activity. Herein, we discuss how immune checkpoint inhibitors may respond to this exhaustion. While most findings showing that these therapies partially restore mitochondrial bioenergetics in T cells have been conducted in preclinical studies, direct clinical evidence in HCC patients remains limited. By combining current knowledge on mitochondrial metabolism, immune escape, and treatment resistance, we discuss how targeting mitochondrial pathways may help improve immunotherapy responses and support new combination treatment approaches against HCC. Full article

Background: Shenqi granule (SQG) was used clinically to strengthen the spleen and boost energy, alleviating physical weakness and limb fatigue caused by energy deficiency. However, the specific effects and potential molecular mechanisms of SQG in myocardial infarction (MI) treatment remain to be clarified. Methods: This study thoroughly evaluates SQG’s role in improving MIRI in rats using a biological approach. Network pharmacology, weighted gene co-expression network analysis (WGCNA), receiver operating characteristic (ROC), and immune landscape analysis were used to analyze components and key molecular targets. The therapeutic targets of SQG were then validated through molecular docking, molecular dynamics simulation, and experiments. Results: SQG reduced myocardial infarct size and improved myocardial function in rats. Network pharmacology analysis found that six bioactive compounds in SQG could target four proteins. Using WGCNA and ROC, two key targets of SQG were identified, MMP9 and ADH1C. Importantly, integrating PPI network prediction, molecular docking, and expression correlation analyses, MMP9 and ADH1C demonstrate strong physical binding potential and expression association, suggesting their possible involvement in MIRI-related pathways through the immune microenvironment. Molecular experiments and other methods confirmed that the five active ingredients in SQG (luteolin, quercetin, hederagenin, 7-O-methylisomucronulatol, and stigmasterol) can exert cardioprotective effects by stably binding to MMP9/ADH1C. Conclusions: SQG reduces myocardial infarct volume and enhances myocardial function in MIRI rats, likely via inhibiting MMP9 and ADH1C expression. This suggests SQG’s potential as a therapeutic agent for MI, with findings offering strong scientific support for SQG’s use in cardiovascular disease research. Full article

Female reproductive aging is associated with a progressive decline in oocyte competence and reduced success in assisted reproductive technologies. While chromosomal abnormalities, mitochondrial dysfunction, and DNA damage have been extensively studied, these mechanisms do not fully explain developmental arrest in chromosomally euploid embryos or the variability in embryo competence. Human oocytes enter a transcriptionally quiescent state during meiotic maturation and rely almost entirely on the regulated translation of stored maternal messenger RNAs to support fertilization and early embryonic development until zygotic genome activation. In this context, translational fidelity becomes a critical determinant of proteome integrity and cellular function. Age-related alterations affecting ribosomal RNA integrity, transfer RNA modification, aminoacylation accuracy, and translational regulatory networks may impair the precision, timing, and coordination of protein synthesis. These defects can disrupt essential processes such as spindle assembly, cytoskeletal organization, and early cleavage dynamics, ultimately compromising embryo viability despite chromosomal normality. In addition, the follicular microenvironment, including redox balance, metabolic support, and signaling pathways, plays a crucial upstream role in maintaining translational integrity. This review integrates mechanistic evidence from molecular, cellular, and developmental studies to propose that progressive decline in translational fidelity represents a fundamental and previously underrecognized driver of reproductive aging. Understanding translational control as a central regulator of oocyte competence may provide new insights into unexplained IVF failure and support the development of novel biomarkers and therapeutic strategies aimed at preserving reproductive potential. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is a primary malignancy often driven by metabolic syndrome, fatty liver disease, and chronic hepatitis. These conditions foster a pro-inflammatory microenvironment that promotes tumor progression. Viniferin, a natural oligostilbene, has gained attention for its potential bioactivity. This study utilized an in silico network pharmacology approach to elucidate the pharmacokinetic properties and molecular mechanisms of ε- and δ-viniferin against HCC within the context of metabolic and inflammatory liver pathologies. Methods: ADMET profiles were characterized using SwissADME and pkCSM. Therapeutic targets were identified by intersecting viniferin-associated molecules with disease genes from GeneCards. A protein–protein interaction (PPI) network was constructed, supplemented by GO and KEGG enrichment analyses. Molecular docking and 200 ns of molecular dynamics (MD) simulations evaluated the binding affinity and structural stability between viniferin isomers and identified hub proteins. Results: Both ε- and δ-viniferin showed favorable drug-like properties, including high gastrointestinal absorption and low hepatotoxicity. We identified 247 overlapping targets, with network analysis highlighting ten essential hub genes, including AKT1, HSP90AA1, ESR1, HIF1A, NFKB1, GSK3B, PTGS2, APP, MTOR, and PIK3CA. Enrichment analysis confirmed their involvement in critical oncogenic pathways. Molecular docking showed strong interactions with APP, HSP90AA1, and AKT1, while MD simulations validated the long-term stability of ε-viniferin within the APP binding pocket. Conclusions: These findings provide mechanistic insights into viniferin as a multi-target agent for HCC, justifying further experimental validation in pre-clinical models. Full article

The skin, the largest organ in the human body, serves as a crucial barrier against external stimuli. With the acceleration of social industrialization and the worsening of global climate change, the risk of physical, chemical and biological damage to the skin has significantly increased. Among these, surgical wounds, accidental injuries, diabetic wounds, and ultraviolet (UV)-radiation-induced photoaging are particularly common. Cutaneous wound healing is a complex and dynamic process that requires precise coordination of numerous molecular events to effectively repair damaged skin. Skin photoaging, a phenomenon of premature aging caused by long-term UV exposure, is characterized by pigmentary abnormalities, telangiectasia, epidermal roughness, wrinkle formation, and precancerous lesions, all of which seriously affect skin health and appearance. Extracellular vesicles (EVs), a class of nano-sized vesicles secreted by various cells, play important regulatory roles in tissue regeneration. Although cell-culture-medium-derived EVs (C-EVs) have been proven to effectively promote skin wound healing and photodamage repair, their origin from a single cell type and challenges in large-scale production severely limit their broad application. In contrast, EVs derived from natural biological resources, including tissue-derived EVs (Ti-EVs) and plant-derived EVs (PDEVs), have emerged as novel therapeutic strategies for skin wounds and photoaging. These EVs better reflect the physiological microenvironment and demonstrate considerably higher production efficiencies. Ti-EVs, obtained from mammalian tissues composed of multiple cell types and extracellular matrix, contain more abundant regulatory factors, thus exhibiting superior bioactivity compared with C-EVs. PDEVs have also garnered significant attention due to their favorable stability, low immunogenicity, unique natural antioxidant components, and feasibility of large-scale extraction. This review will systematically elaborate on the characteristics and isolation methods of both Ti-EVs and PDEVs, as well as their therapeutic roles and underlying mechanism in wound healing and skin photoaging. Full article

Current in vitro tissue models struggle to recapitulate the structural, vascular, and mechanical complexity of human tissues, limiting their physiological relevance for disease modelling and preclinical testing. Self-organising three-dimensional cultures such as spheroids and organoids capture key aspects of cellular organisation and differentiation, but they commonly lack controlled geometry, perfusable vasculature, and reproducible mechanical microenvironments. Conversely, biofabrication strategies, such as three-dimensional (3D) bioprinting and organ-on-chip (OoC) microfluidic devices, offer spatial control, integrated perfusion, and dynamic mechanical stimulation, yet often fall short in recapitulating the full cellular diversity and self-organisation of native tissues. Notably, emerging hybrid approaches that embed self-organising biological units (e.g., organoids and spheroids) into engineered scaffolds or microfluidic platforms combine biological relevance, architectural fidelity, and functional control. Advances in bioink chemistry, sacrificial-printing vascularisation, and chip–organoid interfaces now enable perfusable, multicompartment tissues suitable for disease modelling and preclinical testing. This review highlights the most recent (2020–2025) progress in organoid vascularisation, bioprinting strategies for prevascularised constructs, and OoC integration, outlining remaining challenges and emphasising priorities for next-generation hybrid cellular and tissue models. Full article